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Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation

  1. Kurinchi Selvan Gurusamy1,*,
  2. Emmanuel Tsochatzis2,
  3. Clare D Toon3,
  4. Brian R Davidson1,
  5. Andrew K Burroughs4

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 2 DEC 2013

Assessed as up-to-date: 14 FEB 2013

DOI: 10.1002/14651858.CD006573.pub3


How to Cite

Gurusamy KS, Tsochatzis E, Toon CD, Davidson BR, Burroughs AK. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD006573. DOI: 10.1002/14651858.CD006573.pub3.

Author Information

  1. 1

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

  2. 2

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

  3. 3

    West Sussex County Council, Public Health, Chichester, West Sussex, UK

  4. 4

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

*Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital,, Rowland Hill Street, London, NW3 2PF, UK. kurinchi2k@hotmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 2 DEC 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Belli 2001

MethodsRandomised clinical trial.


ParticipantsCountry: Italy.
Sample size: 19.
Post-randomisation drop-out: unclear.
Revised sample size: 19.
Females: not stated.
Mean age: not stated.
Genotype 1 (intervention): not stated.
Genotype 1 (control): not stated.
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Liver transplantation for HCV infection.
Exclusion criteria:
1. Early transplant deaths.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: ribavirin (n = 11).
Further details: 400 to 600 mg/day orally.
Group 2: control (n = 8).

Timing of commencement of treatment: as soon as patients could tolerate food.


OutcomesGraft rejection and adverse effects of drug.


NotesReasons for post-randomisation drop-out: initially 37 patients were randomised to 1 of 3 groups. Only 2 groups were included for this review. Overall, 7 patients died. It is not clear how many died in each group. Hence, these data could not be used in our review.

Attempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs could be related to the outcomes.

Selective reporting (reporting bias)High riskComment: important outcomes such as mortality and retransplantation were not reported.

Free from source of funding bias?Unclear riskComment: this information was not available.

Chalasani 2005

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 54.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 54.
Females: 11 (20.4%).
Mean age: 53 years.
Genotype 1 (intervention): 19 (73.1%).
Genotype 1 (control): 21 (75%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. HCV infected liver transplant recipients.
2. Alanine aminotransferase > 1.5 times before liver transplantation.
3. No histological evidence of rejection at 3 weeks after transplantation.
Exclusion criteria:
1. Prior interferon therapy.
2. Neutrophil count 1500/μL; haemoglobin < 10 g/dL.
3. Creatinine > 2.0 mg/dL.
4. Cirrhosis.
5. Cholestatic fibrosing hepatitis.
6. Uncontrolled epilepsy.
7. Alcohol or drug abuse within 1 year of entry.
8. Severe psychiatric illness.
9. Immune disorder.
10. Chronic obstructive pulmonary disease.
11. Cardiac disease.
12. Poorly controlled thyroid disease.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: pegylated interferon alpha 2a (n = 26).
Further details: 180 μg/weekly SC for 48 weeks.
Group 2: control (n = 28).

Timing of commencement of treatment: 3 weeks after liver transplantation.


OutcomesMortality, graft rejection, and adverse effects.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: fibrosis and activity scores reported only in 12 patients in the intervention group and 11 patients in the control group.

Selective reporting (reporting bias)High riskComment: important outcomes such as retransplantation were not reported.

Free from source of funding bias?High riskQuote: "supported by a grant from Roche Laboratories Inc., Nutley, NJ".

Charlton 2007

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 115.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 115.
Females: 22 (19.1%).
Mean age: 59 years.
Genotype 1 (intervention): 43 (78.2%).
Genotype 1 (control): 48 (80%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Patients at 10 to 26 weeks of liver transplantation without histological recurrence.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: pegylated interferon alpha 2a plus ribavirin (n = 54).
Further details: interferon: 135 μg/week for 4 weeks followed by 180 μg/week for 44 weeks; ribavirin: 400 mg/day escalating to 1200 mg/day for 48 weeks.
Group 2: control (n = 48).

Timing of commencement of treatment: 10 to 26 weeks after liver transplantation.


OutcomesMortality, graft rejection, and adverse effects.


NotesReason for post-randomisation drop-outs: not stated.

Attempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation dropouts could be related to outcomes.

Selective reporting (reporting bias)High riskComment: important outcomes such as retransplantation were not reported.

Free from source of funding bias?High riskQuote: "Grant/Research Support: Roche".

Chung 2013

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Number randomised: 13.
Post-randomisation drop-outs: 2 (15.4%).
Revised sample size: 11.
Females: 2 (18.2%).

Mean age: 59 years.
Genotype 1 (intervention): 6 (100%).
Genotype 1 (control): 5 (100%).
Growth factors for bone marrow suppression: not applicable.
Inclusion criteria:
1. ≥ 18 years old.
2. HCV genotype 1a-infected.
3. Undergoing liver transplantation from deceased or living-related donors.
Exclusion criteria:
1. HIV or HBV co-infection.
2. Antiviral drugs or immunoglobulin within 90 days.
3. Hepatocellular carcinoma outside the Milan criteria.
4. Personal or family history of deep venous thrombosis or pulmonary embolism.
5. Creatinine > 2.5 mg/dL for ≥ 6 months.
6. Retransplantation or planned combined organ transplant.
7. Receipt of an allograft donated after cardiac death or from an HBV- or HCV-infected donor. 


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: human monoclonal antibody (MBL-HCV1) (n = 6).
Further details: 50 mg/kg; 3 infusions on the day of liver transplantation (1-4 hours before anhepatic phase), during anhepatic phase, and 8 hours post-reperfusion; daily infusions between day 1 and day 7 post-liver transplant; and final infusion on day 14 post-liver transplantation.
Group 2: placebo (n = 5).
Further details: normal saline.

Timing of commencement of treatment: day of liver transplantation.


OutcomesMortality and adverse effects.


NotesReasons for post-randomisation drop-outs: did not undergo transplantation (n = 1); did not receive treatment (n = 1).

Attempted to contact the authors in February 2013. No replies were received.

Consent for liver donation: not stated. The study report stated that ethical approval was obtained for the research.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "This randomized, double-blind, placebo-controlled trial was conducted at eight transplant centers between August 2010 and June 2011….The study sponsor, investigators, subjects and laboratory personnel were blinded to treatment assignment".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: there were post-randomisation drop-outs.

Selective reporting (reporting bias)High riskComment: important outcomes such as retransplantation were not reported.

Free from source of funding bias?High riskQuote: "This study was funded by MassBiologics, University of Massachusetts, Boston, MA. CTSA grant (UL1TR000067) awarded to Mt. Sinai School of Medicine for CRC research support. RTC was supported in part by NIH DK078772".

Davis 2005

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 18.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 18.
Females: 7 (38.9%).
Mean age: 54 years.
Genotype 1 (intervention 1): 5 (83.3%).
Genotype 1 (intervention 2): 4 (66.7%).
Genotype 1 (control): 5 (83.3%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Adults with decompensated chronic hepatitis C who were listed for liver transplant.
Exclusion criteria:
1. Immunoglobulin A deficient.
2. History of prior adverse reactions to immune globulin.
3. Hepatitis B surface antigen or anti-HIV-positive.
4. Extrahepatic malignancy.
5. Receiving cancer chemotherapy.
6. Renal insufficiency.
7. Previously received an organ transplant.
8. Received a graft from an HCV-positive donor.
9. Received any antiviral agents for hepatitis C in the previous 3 months.


InterventionsThe participants were randomly assigned to 1 of 3 groups.
Group 1: human hepatitis C antibody-enriched immune globulin (n = 6).
Further details: 17 intravenous infusions of 200 mg/kg starting at the time of reperfusion of graft until 14 weeks after transplant.
Group 2: human hepatitis C antibody-enriched immune globulin (n = 6).
Further details: 17 intravenous infusions of 75 mg/kg starting at the time of reperfusion of graft until 14 weeks after transplant.
Group 3: control (n = 6).

Timing of commencement of treatment: reperfusion of graft during liver transplantation.


OutcomesMortality, retransplantation, and fibrosis worsening.


NotesAttempted to contact the authors in September 2010. Authors provided replies related to randomisation.

Consent for liver donation: not stated. The study report stated that ethical approval was obtained for the research.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomization sequence was computer generated" (author replies).

Allocation concealment (selection bias)Low riskQuote: "Each site held a sequence in sealed envelopes held by the pharmacy" (author replies).

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs.

Selective reporting (reporting bias)Low riskComment: important outcomes such as mortality and retransplantation were reported.

Free from source of funding bias?High riskQuote: "C.V.S. (one of the authors) is an employee of Nabi Biopharmaceuticals".

Mazzaferro 2003

MethodsRandomised clinical trial.


ParticipantsCountry: Italy.
Sample size: 63.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 63.
Females: 15 (23.8%).
Mean age: 53 years.
Genotype 1 (intervention): not stated.
Genotype 1 (control): not stated.
Overall genotype 1 (individual groups not stated): 42 (66.7%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Liver transplant recipients within 4 weeks after transplant for HCV cirrhosis.
Exclusion criteria:
1. Recurrent hepatitis.
2. Rejection.


InterventionsThe participants were randomly assigned to 1 of 3 groups.
Group 1: ribavirin plus interferon (n = 22).
Further details: ribavirin 10 mg/kg/day; interferon 3 million units IM 3 times weekly (duration not stated).
Group 2: interferon (n = 21).
Further details: 3 million units IM 3 times weekly (duration not stated).
Group 3: control (n = 20).

Timing of commencement of treatment: within 4 weeks after liver transplantation.


OutcomesGraft rejection.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs.

Selective reporting (reporting bias)High riskComment: important outcomes such as mortality and retransplantation were not reported.

Free from source of funding bias?Unclear riskComment: this information was not available.

Reddy 2002

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 32.
Post-randomisation drop-out: not stated.
Revised sample size: 32.
Females: 13 (40.6%).
Mean age: 50 years.
Genotype 1 (intervention): not stated.
Genotype 1 (control): not stated.
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Liver transplantation for HCV infection.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: interferon alpha 2b plus ribavirin (n = 21).
Further details: interferon: 1.5 million units increased to 3 million units 3 times weekly SC; ribavirin 400 mg increased to 1000 mg/day.
Group 2: control (n = 11).

Timing of commencement of treatment: 2-4 weeks after liver transplantation.


OutcomesAdverse effects.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available.

Selective reporting (reporting bias)High riskComment: important outcomes such as mortality and retransplantation were not reported.

Free from source of funding bias?Unclear riskComment: this information was not available.

Schiano 2006

MethodsRandomised clinical trial.


ParticipantsCountry: USA/ Israel.
Sample size: 24.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 24.
Females: 1 (4.2%).
Mean age: 50.8 years.
Genotype 1 (intervention 1): 7 (87.5%).
Genotype 1 (intervention 2): 9 (81.8%).
Genotype 1 (control): 5 (100%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. 18-65 years of age.
2. Primary liver transplantation for HCV infection.
3. HCV RNA positive before liver transplantation by HCV RNA concentration above the local limit of detection within 1 year.
4. Acceptable methods of contraception.
Exclusion criteria:
1. Previous liver transplant recipients.
2. Pregnant or breast-feeding.
3. HIV infection or chronic HBV infection within 1 year.
4. Concurrent transplantation in addition to liver transplantation.


InterventionsThe participants were randomly assigned to 1 of 3 groups.
Group 1: HCV-antibody 68 (high dose) (n = 8).
Further details: 120 or 240 or 480 mg intravenous starting from the anhepatic phase until 8 weeks after transplantation.
Group 2: HCV-antibody 68 (low dose) (n = 11).
Further details: 20 or 40 or 80 mg intravenous starting from the anhepatic phase until 8 weeks after transplantation.
Group 3: placebo (n = 5).

Timing of commencement of treatment: anhepatic phase of liver transplantation.


OutcomesMortality.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated. The study report stated that ethical approval was obtained for the research.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "This was a multicenter, randomised, double-blind, placebo-controlled, dose-escalation trial".

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs.

Selective reporting (reporting bias)High riskComment: important outcomes such as retransplantation were not reported.

Free from source of funding bias?High riskQuote: "Supported by XTL Biopharmaceuticals Ltd., the developer of HCV-AbXTL68".

Sheiner 1998

MethodsRandomised clinical trial.


ParticipantsCountry: USA, Israel.
Sample size: 86.
Post-randomisation drop-out: 5 (5.8%).
Revised sample size: 81.
Females: not stated.
Mean age: not stated.
Genotype 1 (intervention): 21 (60.0%).
Genotype 1 (control): 19 (41.3%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Liver transplantation with positive serology for hepatitis C antibody.
2. Age > 18 years.
Exclusion criteria:
1. Retransplantation for recurrent hepatitis C.
2. Transplantation for hepatitis C with hepatocellular carcinoma requiring adjuvant chemotherapy (ie, tumour 0.5 cm or with vascular invasion).
3. Positive serology for hepatitis B surface antigen.
4. Platelet count < 50,000/mm3by day 14 after transplantation.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: interferon alpha 2b (n = 35).
Further details: 3 million units SC 3 times weekly for 52 weeks.
Group 2: control (n = 46).

Timing of commencement of treatment: within 2 weeks after liver transplantation.


OutcomesMortality, retransplantation, graft rejection, and recurrence of viral hepatitis.


NotesReasons for post-randomisation drop-out: low white cell count (n = 3); adjuvant chemotherapy (n = 1); refusal to enter (n = 1).

Attempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated. The study report stated that ethical approval was obtained for the research.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "Protocol biopsies were also reviewed by three pathologists blinded to study group".
Comment: the other outcomes were not assessed by blinded observers.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs could be related to the outcomes.

Selective reporting (reporting bias)Low riskComment: important outcomes such as mortality and retransplantation were reported.

Free from source of funding bias?High riskQuote: "Supported in part by Ortho Biotech, Raritan, NJ".

Shergill 2005

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 44.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 44.
Females: not stated.
Mean age: not stated.
Genotype 1 (intervention): not stated.
Genotype 1 (control): not stated.
Growth factors for bone marrow suppression: yes.
Inclusion criteria:
1. ≥ 18 years of age.
2. Pretransplant diagnosis of HCV-associated cirrhosis.
3. Clinical stability with white cell count > 3.0/mm3.
4. Haemoglobin > 10.0 g/dL.
5. Platelets > 45,000/mm3.
6. Creatinine < 1.5 mg/dL.
7. International Normalised Ratio < 2.0.
8. Aspartate aminotransferase < 200 IU.
9. Alanine aminotransferase < 200 IU.
10. Total bilirubin < 2.5 mg/dL.
Exclusion criteria:
1. Serum anti-HIV or hepatitis B surface antigen positive prior to transplantation.
2. Acute rejection (by clinical and histological criteria) within 14 days of consent.
3. Vascular and biliary complications post-transplantation resulting in need for interventions.
4. Current untreated infection.
5. Abnormal thyroid-stimulating hormone.
6. Medically uncontrolled psychosis or depression.
7. History of haemoglobinopathies or any cause of chronic haemolysis.
8. Clinically significant retinopathy.
9. Uncontrolled diabetes mellitus.
10. Inability to practice effective contraception (male or female) during the treatment period.
11. Medical history of concomitant autoimmune disease.
12. Continued need for intensive care unit support or unstable cardiopulmonary status including myocardial infarction within preceding 4 weeks.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: ribavirin plus interferon (n = 22).
Further details: ribavirin: 400 mg escalated to 1000 to 1200 mg for a total period of 48 weeks; interferon: interferon alpha 2b or pegylated interferon alpha 2b (initial patients treated with interferon and later patients treated with pegylated interferon). Interferon started at 1.5 million units daily and increased to 3 million units daily after 2 weeks if tolerated. After 8 weeks, 3 million units 3 times weekly. Pegylated interferon: 1.5 μg/kg/week.
Group 2: interferon (n = 22).

Timing of commencement of treatment: 2 to 6 weeks after liver transplantation.


OutcomesNone of the outcomes of interest for this review were reported in this trial.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs.

Selective reporting (reporting bias)High riskComment: important outcomes such as mortality and retransplantation were not reported.

Free from source of funding bias?High riskQuote: "The study was supported by Fugisawa Healthcare, Inc., and the UCSF Liver Center P30 DK26743 Clinical and Translational Core".

Singh 1998

MethodsRandomised clinical trial.


ParticipantsCountry: USA.
Sample size: 24.
Post-randomisation drop-out: 0 (0%).
Revised sample size: 24.
Females: 0 (0%).
Mean age: 46 years.
Genotype 1 (intervention): 9 (75.0%).
Genotype 1 (control): 11 (91.7%).
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Liver transplantation for end-stage liver disease due to HCV.


InterventionsThe participants were randomly assigned to 1 of 2 groups.
Group 1: interferon alpha (n = 12).
Further details: 3 million units 3 times weekly for 6 months.
Group 2: control (n = 12).

Timing of commencement of treatment: 2 weeks after liver transplantation.


OutcomesMortality, retransplantation, graft rejection, and recurrence.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated. The study report stated that ethical approval was obtained for the research.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs.

Selective reporting (reporting bias)Low riskComment: important outcomes such as mortality and retransplantation were reported.

Free from source of funding bias?Unclear riskComment: this information was not available.

Willems 2002

MethodsRandomised clinical trial.


ParticipantsCountry: Canada.
Sample size: 16.
Post-randomisation drop-out: not stated.
Revised sample size: 16.
Females: not stated.
Mean age: not stated.
Genotype 1 (intervention): not stated.
Genotype 1 (control): not stated.
Growth factors for bone marrow suppression: no.
Inclusion criteria:
1. Patients undergoing liver transplantation for end-stage post-HCV cirrhosis.


InterventionsThe participants were randomly assigned to 1 of 3 groups.
Group 1: human hepatitis C antibody-enriched immune globulin (n = 6).
Further details: starting at anhepatic phase with 1500 mg and maintained at 250 mg twice weekly for 48 weeks.
Group 2: human hepatitis C antibody-enriched immune globulin (n = 3).
Further details: starting at anhepatic phase with 500 mg and maintained at 83 mg twice weekly for 48 weeks.
Group 3: placebo (n = 7).

Timing of commencement of treatment: anhepatic phase of liver transplantation.


OutcomesNone of the outcomes of interest for this review were reported in this trial.


NotesAttempted to contact the authors in September 2010. No replies were received.

Consent for liver donation: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available.

Allocation concealment (selection bias)Unclear riskComment: this information was not available.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Twenty-six HCV-RNA positive OLT [orthotopic liver transplantation] candidates were randomly assigned at the time of transplantation to one of three treatment schedules in a double-blind fashion".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available.

Selective reporting (reporting bias)High riskComment: important outcomes such as mortality and retransplantation were not reported.

Free from source of funding bias?Unclear riskComment: this information was not available.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Beckebaum 2003Not a randomised clinical trial.

Boillot 1995Not a randomised clinical trial.

Casanovas 2004Comment on a trial of antiviral therapy in patients with recurrent hepatitis C virus infection after liver transplantation.

Castedal 2003Not a randomised clinical trial.

Catalano 2003Not a randomised clinical trial.

Ceccherini 2003Not a randomised clinical trial.

Charlton 2002Editorial.

Everson 2013No separate data for patients involved in the randomised clinical trial.

Garcia-Retortillo 2004Review.

Mazzaferro 1997Not a randomised clinical trial.

Roche 2011Editorial.

Samuel 2004aEditorial.

Samuel 2004bComments on trial in patients with recurrent hepatitis C virus infection after liver transplantation.

Taltavull 2004Comment on a trial of antiviral therapy in patients with recurrent hepatitis C virus infection after liver transplantation.

 
Comparison 1. Intervention versus control

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

 1 90-day mortality5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Interferon vs. no intervention
181Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.41, 4.19]

    1.2 Pegylated interferon plus ribavirin vs. no intervention
1115Risk Ratio (M-H, Fixed, 95% CI)1.82 [0.46, 7.25]

    1.3 HCV antibody vs. placebo
353Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.15, 3.11]

    1.4 HCV antibody (high dose) vs. HCV antibody (low dose)
231Risk Ratio (M-H, Fixed, 95% CI)2.75 [0.30, 25.35]

 2 Mortality at maximal follow-up3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Interferon vs. no intervention
2105Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.36, 2.08]

    2.2 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.05, 5.59]

 3 Mortality (hazard ratio)1Hazard Ratio (Fixed, 95% CI)Subtotals only

    3.1 Interferon vs. no intervention
1Hazard Ratio (Fixed, 95% CI)0.45 [0.13, 1.56]

 4 90-day retransplantation1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 HCV antibody vs. placebo
118Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.09, 32.93]

    4.2 HCV antibody (high dose) vs. HCV antibody (low dose)
112Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.15, 61.74]

 5 Retransplantation at maximal follow-up2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Interferon vs. no intervention
2105Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.22, 6.20]

 6 Serious adverse events3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.47, 2.00]

    6.2 Pegylated interferon plus ribavirin vs. no intervention
1115Risk Ratio (M-H, Fixed, 95% CI)1.79 [1.03, 3.12]

    6.3 HCV antibody vs. placebo
111Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.03, 1.31]

 7 Anaemia4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Interferon plus ribavirin vs. no intervention
132Risk Ratio (M-H, Fixed, 95% CI)13.64 [0.88, 210.72]

    7.2 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.09, 2.03]

    7.3 Pegylated interferon plus ribavirin vs. no intervention
1100Risk Ratio (M-H, Fixed, 95% CI)11.07 [1.51, 81.47]

    7.4 Ribavirin vs. no intervention
119Risk Ratio (M-H, Fixed, 95% CI)6.75 [0.41, 110.01]

 8 Leukopenia4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Interferon vs. no intervention
124Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.27, 94.34]

    8.2 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.45, 3.73]

    8.3 Pegylated interferon plus ribavirin vs. no intervention
1100Risk Ratio (M-H, Fixed, 95% CI)3.98 [1.22, 12.98]

    8.4 HCV monoclonal antibody vs. placebo
111Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.03, 1.31]

 9 Graft rejection requiring retransplantation1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 Interferon vs. no intervention
131Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.2 Interferon plus ribavirin vs. no intervention
132Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.3 Ribavirin plus interferon vs. interferon
143Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Graft rejection requiring steroids or equivalent drugs4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Interferon vs. no intervention
3136Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.51]

    10.2 Interferon plus ribavirin vs. no intervention
132Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.3 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.20, 3.27]

    10.4 Ribavirin plus interferon vs. interferon
143Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Graft rejection (others)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Interferon vs. no intervention
131Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.2 Interferon plus ribavirin vs. no intervention
132Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.3 Pegylated interferon vs. no intervention
154Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.01, 4.28]

    11.4 Pegylated interferon plus ribavirin vs. no intervention
1115Risk Ratio (M-H, Fixed, 95% CI)1.64 [0.49, 5.49]

    11.5 Ribavirin vs. no intervention
119Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.23, 5.09]

    11.6 Ribavirin plus interferon vs. interferon
143Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Fibrosis worsening1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 HCV antibody vs. placebo
118Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.17, 4.43]

    12.2 HCV antibody (high dose) vs. HCV antibody (low dose)
112Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 6.86]

 13 Recurrence (hazard ratio)2Hazard Ratio (Fixed, 95% CI)Subtotals only

    13.1 Interferon vs. no intervention
2Hazard Ratio (Fixed, 95% CI)0.87 [0.61, 1.24]

 
Summary of findings for the main comparison. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (mortality)

Mortality

Patient or population: patients undergoing liver transplantation for chronic hepatitis C viral infection.
Settings: tertiary.
Comparisons: shown in table.

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

Assumed riskCorresponding risk

ControlIntervention

Interferon vs. control

90-day mortality109 per 1000142 per 1000
(45 to 455)
RR 1.31
(0.41 to 4.19)
81
(1 study)
⊕⊝⊝⊝
very low1,2

Mortality at maximal follow-up 172 per 1000148 per 1000
(62 to 359)
RR 0.86
(0.36 to 2.08)
105
(2 studies)
⊕⊝⊝⊝
very low1,2

Mortality (HR)
Follow-up: mean 12 months
100 per 100046 per 1000
(14 to 152)
HR 0.45
(0.13 to 1.56)
81
(1 study)
⊕⊝⊝⊝
very low1,2

Pegylated interferon vs. control

Mortality at maximal follow-up 71 per 100039 per 1000
(4 to 399)
RR 0.54
(0.05 to 5.59)
54
(1 study)
⊕⊝⊝⊝
very low1,2

Pegylated interferon plus ribavirin vs. control

90-day mortality50 per 100091 per 1000
(23 to 362)
RR 1.82
(0.46 to 7.25)
115
(1 study)
⊕⊝⊝⊝
very low1,2

HCV antibody vs. placebo

90-day mortality62 per 100043 per 1000
(9 to 194)
RR 0.69
(0.15 to 3.11)
53
(3 studies)
⊕⊝⊝⊝
very low1,2

HCV antibody (high dose) vs. HCV antibody (low dose)

90-day mortality 59 per 1000162 per 1000
(18 to 1000)
RR 2.75
(0.3 to 25.35)
31
(2 studies)
⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk is the control group risk across studies. 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; HCV: hepatitis C virus; RR: risk ratio; HR: hazard 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 CIs 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.
 
Summary of findings 2. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (retransplantation)

Retransplantation

Patient or population: patients undergoing liver transplantation for chronic hepatitis C viral infection.
Settings: tertiary.
Comparisons: shown in table.

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

Assumed riskCorresponding risk

ControlIntervention

Interferon vs. control

Retransplantation at maximal follow-up 34 per 100040 per 1000
(8 to 214)
RR 1.17
(0.22 to 6.2)
105
(2 studies)
⊕⊝⊝⊝
very low1,2

HCV antibody vs. placebo

90-day retransplantation30 per 100051 per 1000
(3 to 988)
RR 1.71
(0.09 to 32.93)
18
(1 study)
⊕⊝⊝⊝
very low1,2

HCV antibody (high dose) vs. HCV antibody (low dose)

90-day retransplantation30 per 100090 per 1000
(5 to 1000)
RR 3
(0.15 to 61.74)
12
(1 study)
⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk for interferon versus control was the control group risk in the studies. There were no events in the control group for the other two comparisons. So, the control group risk in the interferon versus control comparison was used as the assumed risk. 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; HCV: hepatitis C virus; 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 CIs 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.