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

Kurinchi Selvan Gurusamy; Emmanuel Tsochatzis; Clare D Toon; Brian R Davidson; Andrew K Burroughs

doi:10.1002/14651858.CD006573.pub3

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

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Referencias

References to studies included in this review

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References to other published versions of this review

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estudios incluidos
estudios excluidos
otras referencias

Gurusamy KS, Tsochatzis E, Davidson BR, Burroughs AK. Antiviral prophylactic intervention for chronic hepatitis C virus in patients undergoing liver transplantation. Cochrane Database of Systematic Reviews 2010, Issue 12. [DOI: 10.1002/14651858.CD006573.pub2]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Belli 2001

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Graft rejection and adverse effects of drug.
Notes	Reasons 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: post‐randomisation drop‐outs could be related to the outcomes.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	Unclear risk	Comment: this information was not available.

Chalasani 2005

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality, graft rejection, and adverse effects.
Notes	Attempted to contact the authors in September 2010. No replies were received. Consent for liver donation: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 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 risk	Comment: important outcomes such as retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "supported by a grant from Roche Laboratories Inc., Nutley, NJ".

Charlton 2007

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality, graft rejection, and adverse effects.
Notes	Reason 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: post‐randomisation dropouts could be related to outcomes.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "Grant/Research Support: Roche".

Chung 2013

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality and adverse effects.
Notes	Reasons 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "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 risk	Comment: there were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "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

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality, retransplantation, and fibrosis worsening.
Notes	Attempted 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization sequence was computer generated" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "Each site held a sequence in sealed envelopes held by the pharmacy" (author replies).
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Low risk	Comment: important outcomes such as mortality and retransplantation were reported.
Free from source of funding bias?	High risk	Quote: "C.V.S. (one of the authors) is an employee of Nabi Biopharmaceuticals".

Mazzaferro 2003

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Graft rejection.
Notes	Attempted to contact the authors in September 2010. No replies were received. Consent for liver donation: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	Unclear risk	Comment: this information was not available.

Reddy 2002

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Adverse effects.
Notes	Attempted to contact the authors in September 2010. No replies were received. Consent for liver donation: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: this information was not available.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	Unclear risk	Comment: this information was not available.

Schiano 2006

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality.
Notes	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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "This was a multicenter, randomised, double‐blind, placebo‐controlled, dose‐escalation trial".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "Supported by XTL Biopharmaceuticals Ltd., the developer of HCV‐AbXTL68".

Sheiner 1998

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality, retransplantation, graft rejection, and recurrence of viral hepatitis.
Notes	Reasons 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "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 risk	Comment: post‐randomisation drop‐outs could be related to the outcomes.
Selective reporting (reporting bias)	Low risk	Comment: important outcomes such as mortality and retransplantation were reported.
Free from source of funding bias?	High risk	Quote: "Supported in part by Ortho Biotech, Raritan, NJ".

Shergill 2005

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempted to contact the authors in September 2010. No replies were received. Consent for liver donation: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "The study was supported by Fugisawa Healthcare, Inc., and the UCSF Liver Center P30 DK26743 Clinical and Translational Core".

Singh 1998

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	Mortality, retransplantation, graft rejection, and recurrence.
Notes	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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: this information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Low risk	Comment: important outcomes such as mortality and retransplantation were reported.
Free from source of funding bias?	Unclear risk	Comment: this information was not available.

Willems 2002

Methods	Randomised clinical trial.
Participants	Country: 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.
Interventions	The 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.
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempted to contact the authors in September 2010. No replies were received. Consent for liver donation: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "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 risk	Comment: this information was not available.
Selective reporting (reporting bias)	High risk	Comment: important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	Unclear risk	Comment: this information was not available.

HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IM: intramuscular; RNA: ribonucleic acid; SC: subcutaneous.

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Beckebaum 2003	Not a randomised clinical trial.
Boillot 1995	Not a randomised clinical trial.
Casanovas 2004	Comment on a trial of antiviral therapy in patients with recurrent hepatitis C virus infection after liver transplantation.
Castedal 2003	Not a randomised clinical trial.
Catalano 2003	Not a randomised clinical trial.
Ceccherini 2003	Not a randomised clinical trial.
Charlton 2002	Editorial.
Everson 2013	No separate data for patients involved in the randomised clinical trial.
Garcia‐Retortillo 2004	Review.
Mazzaferro 1997	Not a randomised clinical trial.
Roche 2011	Editorial.
Samuel 2004a	Editorial.
Samuel 2004b	Comments on trial in patients with recurrent hepatitis C virus infection after liver transplantation.
Taltavull 2004	Comment on a trial of antiviral therapy in patients with recurrent hepatitis C virus infection after liver transplantation.

Data and analyses

Open in table viewer

Comparison 1. Intervention versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 90‐day mortality Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Intervention versus control, Outcome 1 90‐day mortality.
1.1 Interferon vs. no intervention	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.41, 4.19]
1.2 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.46, 7.25]
1.3 HCV antibody vs. placebo	3	53	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.15, 3.11]
1.4 HCV antibody (high dose) vs. HCV antibody (low dose)	2	31	Risk Ratio (M‐H, Fixed, 95% CI)	2.75 [0.30, 25.35]
2 Mortality at maximal follow‐up Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1 Intervention versus control, Outcome 2 Mortality at maximal follow‐up.
2.1 Interferon vs. no intervention	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.36, 2.08]
2.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.05, 5.59]
3 Mortality (hazard ratio) Show forest plot	1		Hazard Ratio (Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Intervention versus control, Outcome 3 Mortality (hazard ratio).
3.1 Interferon vs. no intervention	1		Hazard Ratio (Fixed, 95% CI)	0.45 [0.13, 1.56]
4 90‐day retransplantation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1 Intervention versus control, Outcome 4 90‐day retransplantation.
4.1 HCV antibody vs. placebo	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.09, 32.93]
4.2 HCV antibody (high dose) vs. HCV antibody (low dose)	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.15, 61.74]
5 Retransplantation at maximal follow‐up Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Intervention versus control, Outcome 5 Retransplantation at maximal follow‐up.
5.1 Interferon vs. no intervention	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.22, 6.20]
6 Serious adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 Intervention versus control, Outcome 6 Serious adverse events.
6.1 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.47, 2.00]
6.2 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.03, 3.12]
6.3 HCV antibody vs. placebo	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.31]
7 Anaemia Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 Intervention versus control, Outcome 7 Anaemia.
7.1 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	13.64 [0.88, 210.72]
7.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.09, 2.03]
7.3 Pegylated interferon plus ribavirin vs. no intervention	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	11.07 [1.51, 81.47]
7.4 Ribavirin vs. no intervention	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	6.75 [0.41, 110.01]
8 Leukopenia Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.8 Comparison 1 Intervention versus control, Outcome 8 Leukopenia.
8.1 Interferon vs. no intervention	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.27, 94.34]
8.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.45, 3.73]
8.3 Pegylated interferon plus ribavirin vs. no intervention	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.98 [1.22, 12.98]
8.4 HCV monoclonal antibody vs. placebo	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.31]
9 Graft rejection requiring retransplantation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.9 Comparison 1 Intervention versus control, Outcome 9 Graft rejection requiring retransplantation.
9.1 Interferon vs. no intervention	1	31	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Graft rejection requiring steroids or equivalent drugs Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.10 Comparison 1 Intervention versus control, Outcome 10 Graft rejection requiring steroids or equivalent drugs.
10.1 Interferon vs. no intervention	3	136	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.68, 1.51]
10.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.3 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.20, 3.27]
10.4 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Graft rejection (others) Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.11 Comparison 1 Intervention versus control, Outcome 11 Graft rejection (others).
11.1 Interferon vs. no intervention	1	31	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.28]
11.4 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.49, 5.49]
11.5 Ribavirin vs. no intervention	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.23, 5.09]
11.6 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Fibrosis worsening Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.12 Comparison 1 Intervention versus control, Outcome 12 Fibrosis worsening.
12.1 HCV antibody vs. placebo	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.17, 4.43]
12.2 HCV antibody (high dose) vs. HCV antibody (low dose)	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.86]
13 Recurrence (hazard ratio) Show forest plot	2		Hazard Ratio (Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.13 Comparison 1 Intervention versus control, Outcome 13 Recurrence (hazard ratio).
13.1 Interferon vs. no intervention	2		Hazard Ratio (Fixed, 95% CI)	0.87 [0.61, 1.24]

Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Figure 4

Trial sequential analysis of 90‐day mortality (hepatitis C virus antibody versus placebo)
The diversity‐adjusted required information size (DARIS) was calculated with 10,577 patients, based on the proportion of patients in the control group with the outcome of 6.3%, 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 53 participants in three trials, only 0.5% of the DARIS was 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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Figure 5

Trial sequential analysis of 90‐day mortality (hepatitis C virus antibody (high dose) versus hepatitis C virus antibody (low dose))
The diversity‐adjusted required information size (DARIS) was calculated with 11,338 patients, based on the proportion of patients in the control group with the outcome of 5.9%, 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 31 participants in two trials, only 0.27% 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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Figure 6

Trial sequential analysis of mortality at maximal follow‐up (interferon versus no intervention)
The diversity‐adjusted required information size (DARIS) was calculated with 3796 patients, based on the proportion of patients in the control no intervention group with the outcome of 17.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 8.54%. 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 105 participants in two trials, only 2.77% 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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Figure 7

Trial sequential analysis of retransplantation at maximal follow‐up (interferon versus no intervention)
The diversity‐adjusted required information size (DARIS) was calculated with 20,141 patients, based on the proportion of patients in the no intervention control group with the outcome of 3.4%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 8.54%. 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 105 participants in two trials, only 0.52% 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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Figure 8

Trial sequential analysis of graft rejection requiring steroids or equivalent drugs (interferon versus no intervention)
The diversity‐adjusted required information size (DARIS) was calculated with 1079 patients, based on the proportion of patients in the no intervention control group with the outcome of 41.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 8.54%. 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 136 participants in three trials, only 12.60% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the trial sequential boundaries (continuous red line) nor the conventional boundaries (dotted red line) have been crossed by the cumulative Z‐curve.

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Analysis 1.1

Comparison 1 Intervention versus control, Outcome 1 90‐day mortality.

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Analysis 1.2

Comparison 1 Intervention versus control, Outcome 2 Mortality at maximal follow‐up.

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Analysis 1.3

Comparison 1 Intervention versus control, Outcome 3 Mortality (hazard ratio).

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Analysis 1.4

Comparison 1 Intervention versus control, Outcome 4 90‐day retransplantation.

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Analysis 1.5

Comparison 1 Intervention versus control, Outcome 5 Retransplantation at maximal follow‐up.

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Analysis 1.6

Comparison 1 Intervention versus control, Outcome 6 Serious adverse events.

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Analysis 1.7

Comparison 1 Intervention versus control, Outcome 7 Anaemia.

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Analysis 1.8

Comparison 1 Intervention versus control, Outcome 8 Leukopenia.

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Analysis 1.9

Comparison 1 Intervention versus control, Outcome 9 Graft rejection requiring retransplantation.

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Analysis 1.10

Comparison 1 Intervention versus control, Outcome 10 Graft rejection requiring steroids or equivalent drugs.

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Analysis 1.11

Comparison 1 Intervention versus control, Outcome 11 Graft rejection (others).

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Analysis 1.12

Comparison 1 Intervention versus control, Outcome 12 Fibrosis worsening.

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Analysis 1.13

Comparison 1 Intervention versus control, Outcome 13 Recurrence (hazard ratio).

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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.
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Intervention
Interferon vs. control
90‐day mortality	109 per 1000	142 per 1000 (45 to 455)	RR 1.31 (0.41 to 4.19)	81 (1 study)	⊕⊝⊝⊝ very low^1,2
Mortality at maximal follow‐up	172 per 1000	148 per 1000 (62 to 359)	RR 0.86 (0.36 to 2.08)	105 (2 studies)	⊕⊝⊝⊝ very low^1,2
Mortality (HR) Follow‐up: mean 12 months	100 per 1000	46 per 1000 (14 to 152)	HR 0.45 (0.13 to 1.56)	81 (1 study)	⊕⊝⊝⊝ very low^1,2
Pegylated interferon vs. control
Mortality at maximal follow‐up	71 per 1000	39 per 1000 (4 to 399)	RR 0.54 (0.05 to 5.59)	54 (1 study)	⊕⊝⊝⊝ very low^1,2
Pegylated interferon plus ribavirin vs. control
90‐day mortality	50 per 1000	91 per 1000 (23 to 362)	RR 1.82 (0.46 to 7.25)	115 (1 study)	⊕⊝⊝⊝ very low^1,2
HCV antibody vs. placebo
90‐day mortality	62 per 1000	43 per 1000 (9 to 194)	RR 0.69 (0.15 to 3.11)	53 (3 studies)	⊕⊝⊝⊝ very low^1,2
HCV antibody (high dose) vs. HCV antibody (low dose)
90‐day mortality	59 per 1000	162 per 1000 (18 to 1000)	RR 2.75 (0.3 to 25.35)	31 (2 studies)	⊕⊝⊝⊝ very low^1,2
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 for the main comparison. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (mortality)

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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.
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Intervention
Interferon vs. control
Retransplantation at maximal follow‐up	34 per 1000	40 per 1000 (8 to 214)	RR 1.17 (0.22 to 6.2)	105 (2 studies)	⊕⊝⊝⊝ very low^1,2
HCV antibody vs. placebo
90‐day retransplantation	30 per 1000	51 per 1000 (3 to 988)	RR 1.71 (0.09 to 32.93)	18 (1 study)	⊕⊝⊝⊝ very low^1,2
HCV antibody (high dose) vs. HCV antibody (low dose)
90‐day retransplantation	30 per 1000	90 per 1000 (5 to 1000)	RR 3 (0.15 to 61.74)	12 (1 study)	⊕⊝⊝⊝ very low^1,2
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.

Summary of findings 2. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (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 90‐day mortality Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Interferon vs. no intervention	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.41, 4.19]
1.2 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.46, 7.25]
1.3 HCV antibody vs. placebo	3	53	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.15, 3.11]
1.4 HCV antibody (high dose) vs. HCV antibody (low dose)	2	31	Risk Ratio (M‐H, Fixed, 95% CI)	2.75 [0.30, 25.35]
2 Mortality at maximal follow‐up Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Interferon vs. no intervention	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.36, 2.08]
2.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.05, 5.59]
3 Mortality (hazard ratio) Show forest plot	1		Hazard Ratio (Fixed, 95% CI)	Subtotals only

3.1 Interferon vs. no intervention	1		Hazard Ratio (Fixed, 95% CI)	0.45 [0.13, 1.56]
4 90‐day retransplantation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 HCV antibody vs. placebo	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.09, 32.93]
4.2 HCV antibody (high dose) vs. HCV antibody (low dose)	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.15, 61.74]
5 Retransplantation at maximal follow‐up Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Interferon vs. no intervention	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.22, 6.20]
6 Serious adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.47, 2.00]
6.2 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.03, 3.12]
6.3 HCV antibody vs. placebo	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.31]
7 Anaemia Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	13.64 [0.88, 210.72]
7.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.09, 2.03]
7.3 Pegylated interferon plus ribavirin vs. no intervention	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	11.07 [1.51, 81.47]
7.4 Ribavirin vs. no intervention	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	6.75 [0.41, 110.01]
8 Leukopenia Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 Interferon vs. no intervention	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.27, 94.34]
8.2 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.45, 3.73]
8.3 Pegylated interferon plus ribavirin vs. no intervention	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.98 [1.22, 12.98]
8.4 HCV monoclonal antibody vs. placebo	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.31]
9 Graft rejection requiring retransplantation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 Interferon vs. no intervention	1	31	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Graft rejection requiring steroids or equivalent drugs Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Interferon vs. no intervention	3	136	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.68, 1.51]
10.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.3 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.20, 3.27]
10.4 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Graft rejection (others) Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1 Interferon vs. no intervention	1	31	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Interferon plus ribavirin vs. no intervention	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 Pegylated interferon vs. no intervention	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.28]
11.4 Pegylated interferon plus ribavirin vs. no intervention	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.49, 5.49]
11.5 Ribavirin vs. no intervention	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.23, 5.09]
11.6 Ribavirin plus interferon vs. interferon	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Fibrosis worsening Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 HCV antibody vs. placebo	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.17, 4.43]
12.2 HCV antibody (high dose) vs. HCV antibody (low dose)	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.86]
13 Recurrence (hazard ratio) Show forest plot	2		Hazard Ratio (Fixed, 95% CI)	Subtotals only

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

Comparison 1. Intervention versus control

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Referencias

References to studies included in this review

Belli 2001 {published data only}

Chalasani 2005 {published data only}

Charlton 2007 {published data only}

Chung 2013 {published data only}

Davis 2005 {published data only}

Mazzaferro 2003 {published data only}

Reddy 2002 {published data only}

Schiano 2006 {published data only}

Sheiner 1998 {published data only}

Shergill 2005 {published data only}

Singh 1998 {published data only}

Willems 2002 {published data only}

References to studies excluded from this review

Beckebaum 2003 {published data only}

Boillot 1995 {published data only}

Casanovas 2004 {published data only}

Castedal 2003 {published data only}

Catalano 2003 {published data only}

Ceccherini 2003 {published data only}

Charlton 2002 {published data only}

Everson 2013 {published data only}

Garcia‐Retortillo 2004 {published data only}

Mazzaferro 1997 {published data only}

Roche 2011 {published data only}

Samuel 2004a {published data only}

Samuel 2004b {published data only}

Taltavull 2004 {published data only}

Additional references

Afdhal 2004

Berenguer 2003

Bombuy 2004

Brok 2008

Brok 2009

Brok 2010

Cameron 2006

Cescon 2006

Corno 2006

CTU 2011

DeMets 1987

DerSimonian 1986

Dieterich 2003

Eason 2001

Egger 1997

Forman 2002

Ghobrial 1999

Gluud 2007

Gluud 2013

Gurusamy 2009

Gurusamy 2013

Higgins 2002

Higgins 2011

ICH‐GCP 1997

Jain 2002

Kamath 2001

Kjaergard 2001

Koneru 2005

Lim 2006

Lundh 2012

Macaskill 2001

Moher 1998

Newell 1992

NHS UK Transplant

OPTN/SRTR 2005

Parmar 1998

RevMan 2012 [Computer program]

Royle 2003

Savovic 2012

Savovic 2012a

Schulz 1995

Sharvadze 2006

Sharvadze 2007

Shiffman 2006

Sugo 2003

Thorlund 2009

Thorlund 2010

Thorlund 2011