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

Abstract

Background

Antiviral therapy for recurrent hepatitis C infection after liver transplantation is controversial due to unresolved balance between benefits and harms.

Objectives

To compare the therapeutic benefits and harms of different antiviral regimens in patients with hepatitis C re‐infected grafts after liver transplantation.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013.

Selection criteria

We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing various antiviral therapies (alone or in combination) in the treatment of hepatitis C virus recurrence in liver transplantation for the review.

Data collection and analysis

Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) using the fixed‐effect and the random‐effects models based on available case‐analysis. In the presence of only trials for a dichotomous outcome, we performed the Fisher's exact test.

Main results

Overall, 17 trials with 736 patients met the inclusion criteria for this review. All trials had high risk of bias. Five hundred and one patients randomised in 11 trials provided information for various comparisons in this systematic review after excluding post‐randomisation drop‐outs and patients from trials that did not report any of the outcomes of interest for this review. The comparisons for which outcomes were available included pegylated (peg) interferon versus control; peg interferon plus ribavirin versus control; ribavirin plus peg interferon versus peg interferon; peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin; amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin; interferon versus control; interferon plus ribavirin versus control; ribavirin versus interferon; and ribavirin versus placebo. Long‐term follow‐up was not available in these trials. There were no significant differences in mortality, retransplantation, graft rejections requiring retransplantation or medical treatment, or fibrosis worsening between the groups in any of the comparisons in which these outcomes were reported. Quality of life and liver decompensation were not reported in any of the trials. There was a significantly higher proportion of participants who developed serious adverse events in the ribavirin plus peg interferon combination therapy group than in the peg interferon monotherapy group (1 trial; 56 participants; 17/28 (60.7%) in the intervention group versus 5/28 (17.9%) in the control group; RR 3.40; 95% CI 1.46 to 7.94). There was no significant difference in proportion of participants who developed serious adverse events or in the number of serious adverse events between the intervention and control groups in the other comparisons that reported serious adverse events.

Authors' conclusions

Considering the lack of clinical benefit, there is currently no evidence to recommend or refute antiviral treatment for recurrent liver graft infection with hepatitis C virus. Further randomised clinical trials with low risk of bias and low risk of random errors with adequate duration of follow‐up are necessary.

Plain language summary

Antiviral therapy for recurrent liver graft infection with hepatitis C virus

Background

The liver is an important organ of the body and has various functions including generation of energy from food; production of material necessary for congealing, processing, and excretion of drugs and waste products in blood; and filtering out the harmful bacteria that enter the body through the gut. Hepatitis C virus can cause damage to the liver usually in an insidious manner (chronic hepatitis C infection). Sometimes, the liver damage can be so severe that the liver is not able to carry out the normal functions, resulting in liver failure. Liver transplantation is an effective treatment for the treatment of liver failure due to chronic hepatitis C infection. However, liver transplantation does not eradicate the virus and the virus can affect the donor liver graft. One of the proposed strategies to treat the recurrence of chronic hepatitis C virus infection in these patients is using antiviral treatments. The effectiveness of these treatments is not known. We performed a detailed review of the medical literature (to February 2013) to determine the benefits and harms of different antiviral treatments for patients with recurrent hepatitis C infection after undergoing liver transplantation for chronic hepatitis C virus infection. We sought evidence from randomised clinical trials only. When conducted properly, such trials provide the best evidence. Two authors independently identified the trials and obtained the information from the trials to minimise error.

Study characteristics

Eleven trials including 501 liver transplant recipients provided data for this review. The patients were randomised to receive different treatments including no treatment in these 11 trials. Long‐term follow‐up was not available in these trials.

Key results

There were no significant differences in the proportion of patients who died, required retransplantation, developed graft rejection that required treatment, or increased liver damage (as evaluated using a microscope) between the groups in any of the comparisons in which these outcomes were reported. Quality of life and liver decompensation were not reported in any of the trials. There was a significantly higher proportion of participants who developed serious complications in the ribavirin plus peg interferon combination therapy compared with peg interferon monotherapy. There was no significant difference in the proportion of participants who developed serious complications or in the number of serious adverse events between the intervention and control groups in the other comparisons that reported serious complications. There is currently no evidence to recommend antiviral treatment for patients with recurrence of chronic hepatitis C virus infection either in primary liver transplantation or retransplantation.

Quality of evidence

All the trials had high risk of systematic errors (that is, bias where was a potential to arrive at wrong conclusions because of the way the trials were conducted overestimating benefits and underestimating harms) and random errors (there was a potential to arrive at the wrong conclusions because of the play of chance). The overall quality of evidence was very low.

Future research

Further randomised clinical trials at low risk of random errors or systematic errors are necessary to assess the long‐term survival and other benefits of various treatment options in these patients.

Summary of findings

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

Mortality
Patient or population: Participants with recurrent liver graft infection with hepatitis C virus. Settings: Secondary or tertiary setting. Intervention: Various interventions. Comparison: Various controls.
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Intervention
Peg interferon vs.control	62 per 1000	30 per 1000 (3 to 318)	RR 0.48 (0.05 to 5.09)	65 (1 study)	⊕⊝⊝⊝ very low1,2	The assumed risk was the control group risk.
Peg interferon plus ribavirin vs.control	63 per 1000	189 per 1000 (8 to 1000)	RR 3 (0.13 to 70.53)	54 (1 study)	⊕⊝⊝⊝ very low1,2	Since there were no deaths in the control group, the assumed risk was the control group risk in a different trial included in this review.
Ribavirin plus peg interferon vs.peg interferon	41 per 1000	20 per 1000 (2 to 212)	RR 0.5 (0.05 to 5.2)	98 (2 studies)	⊕⊝⊝⊝ very low1,2	The assumed risk was the control group risk.
Interferon vs.control	63 per 1000	105 per 1000 (5 to 1000)	RR 1.67 (0.08 to 33.75)	12 (1 study)	⊕⊝⊝⊝ very low1,2	Since there were no deaths in the control group, the assumed risk was the control group risk in a different trial included in this review.
Interferon plus ribavirin vs.control	42 per 1000	12 per 1000 (0 to 281)	RR 0.29 (0.01 to 6.74)	52 (1 study)	⊕⊝⊝⊝ very low1,2	The assumed risk was the control group risk.
Ribavirin vs.interferon	There were no deaths in either group.		Not estimable	30 (1 study)	⊕⊝⊝⊝ very low1,2	‐
Ribavirin vs.placebo	There were no deaths in either group.		Not estimable	77 (1 study)	⊕⊝⊝⊝ very low1,2	‐
*The basis for the assumed risk is provided in the comments section. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; peg: pegylated; RR: risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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

Summary of findings 2. Antiviral therapy for recurrent liver graft infection with hepatitis C virus (retransplantation).

Retransplantation
Patient or population: Participants with recurrent liver graft infection with hepatitis C virus. Settings: Secondary or tertiary setting. Intervention: Various interventions. Comparison: Various controls.
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Intervention
Retransplantation after start of therapy ‐ ribavirin vs.placebo	No retransplantation in either group		Not estimable	77 (1 study)	⊕⊝⊝⊝ very low1,2
Retransplantation after start of therapy ‐ interferon vs.control	10 per 1000	17 per 1000 (1 to 338)	RR 1.67 (0.08 to 33.75)	12 (1 study)	⊕⊝⊝⊝ very low1,2	There was no retransplantation in the control group. So, we used an assumed risk of 1%.
*The basis for the assumed risk is provided in the comments section. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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

Background

In the UK, the annual incidence of liver transplantation is 13 per one million population (NHSBT). In the USA, the annual incidence of liver transplantation is 21 per one million population (OPTN/SRTR 2009). Liver transplant is performed mainly for end‐stage liver failure arising acutely (eg, viruses, drug overdose), or as a result of chronic liver disease (eg, cirrhosis due to alcohol consumption, viruses), or as a result of tumour (Lim 2006). Liver graft can be harvested from living donors (Bombuy 2004), or from cadavers (Koneru 2005; Cescon 2006). Liver transplant can be performed in adults or children (Lim 2006). Worldwide, there is a demand for liver transplants in surplus of supply. Split liver transplantation (using one cadaveric donor liver for two recipients) has been suggested as a way to decrease the organ shortage for liver transplant (Corno 2006).

Hepatitis C viral cirrhosis is one of the main causes for liver transplantation (Eason 2001). Re‐infection of the liver graft is virtually universal in patients who undergo liver transplantation for hepatitis C virus infection. Immunosuppressive regimens that avoid steroids are reported to have a lower rate of graft infection with hepatitis C virus than those that include steroids as part of immunosuppressive therapy (Eason 2001). Azathioprine and anti‐CD3 monoclonal antibody (OKT3) are other immunosuppressive agents that can influence the severity of fibrosis following hepatitis C viral recurrence after liver transplantation (Berenguer 2003). The recurrence rate with hepatitis C virus is also dependent on hepatitis C subtype (with subtype Ib showing a higher recurrence rate than other subtypes) (Sugo 2003); age of the donor (Cameron 2006); age of the recipient (Cameron 2006); model for end‐stage liver disease (MELD) score recipient (Cameron 2006); and warm ischaemic time (Cameron 2006). Antiviral prophylaxis to prevent the recurrence of chronic hepatitis C virus infection does not seem effective (Gurusamy 2013).

Antiviral agents such as ribavirin and interferon have been used to treat hepatitis C virus re‐infection in the liver grafts either alone or in combination (Gane 1998; Chalasani 2005; Duvoux 2006). However, concerns remain about the adverse effects of these agents such as anaemia (Chalasani 2005), haemolysis (Gane 1998), renal failure (Chalasani 2005; Duvoux 2006), depression (Chalasani 2005), and transplant rejection (Chalasani 2005; Duvoux 2006).
 
 Previous reviews have not advocated routine therapy of patients with established recurrence of hepatitis C virus infection in liver transplant recipients (Triantos 2005; Arjal 2007). This is an update of the review published in The Cochrane Library Issue 1, 2010 (Gurusamy 2010), in which we did not recommend routine treatment of patients with established recurrence of hepatitis C virus.

Objectives

To compare the therapeutic benefits and harms of different antiviral regimens in patients with hepatitis C re‐infected grafts after liver transplantation.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised clinical trials that assessed antiviral intervention aimed at treatment of the hepatitis C virus re‐infected liver graft (irrespective of language, blinding, publication status, sample size, or whether the trials were adequately powered or not). We excluded quasi‐randomised trials (where the method of allocating participants to an intervention was not strictly random, eg, date of birth, hospital record number, alternation).

Types of participants

Patients with hepatitis C viral re‐infection of the liver graft (however defined by study authors) irrespective of age, cadaveric or living donor transplant, indication for liver transplantation, first or re‐transplantation, and the immunosuppressive therapy used.

Types of interventions

We included any antiviral treatment in patients with hepatitis C re‐infected liver grafts versus no intervention, placebo, or another antiviral treatment.

We did not include the following interventions:

1. Prophylactic treatment of hepatitis C virus in patients who do not have established re‐infection of the liver graft (ie, pre‐emptive therapy), as this was considered in another review (Gurusamy 2013).

2. Treatment for hepatitis C virus infection while waiting for liver transplant.

Types of outcome measures

Primary outcomes

1. Mortality (30‐days mortality and mortality at maximal follow‐up) after starting the treatment.

2. Re‐transplantation after the start of therapy.

3. Quality of life during and after treatment.

4. Serious adverse events were defined as any event that would increase mortality; were life‐threatening, required inpatient hospitalisation, resulted in a persistent or significant disability, or any important medical event that might have jeopardised the patient or required intervention to prevent it (ICH‐GCP 1997).

Secondary outcomes

1. Hepatic decompensation (bleeding varices, ascites, encephalopathy, coagulation disorders).

2. Rejection of liver transplant after the start of therapy (however defined by authors).

3. Worsening of fibrosis (however defined by authors).

We have provided the summary of findings table for mortality and retransplantation using GRADEpro (ims.cochrane.org/revman/other‐resources/gradepro) and planned to create a summary of findings table for quality of life.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003) to February 2013. We have given the search strategies in with the time spans for the searches in Appendix 1.

Searching other resources

We also searched the references of the identified trials to identify further relevant trials.

Data collection and analysis

Selection of studies

KSG and ET, CT, or EX identified the trials for inclusion independently of each other. The excluded studies with the reasons for the exclusion have been listed.

Data extraction and management

KSG and ET, CT, or EX independently extracted the following data.

1. Year and language of publication.

2. Country.

3. Year of conduct of trial.

4. Inclusion and exclusion criteria.

5. Adult or paediatric.

6. Population characteristics such as recipient age, sex ratio, interval between transplantation and treatment.

7. Number undergoing retransplantation.

8. Immunosuppressive therapy.

9. Other co‐existing viral diseases.

10. Co‐interventions.

11. Viral subtype.

12. Duration of follow‐up.

13. Outcomes (mentioned above).

14. Risk of bias (described below).

We sought any unclear or missing information clarified by contacting the authors of the individual trials. If there was any doubt whether the trials shared the same patients ‐ completely or partially (by identifying common study authors and centres) ‐ we intended to contact the authors of the trials to clarify whether the trial report had been duplicated. However, we had no such instances. It was clear from the multiple reports that they all reported on the same patients.

We resolved any differences in opinion through discussion and in case of unsettled disagreements, BRD adjudicated.

Assessment of risk of bias in included studies

KSG and CT or ET assessed the bias risk of the trials independently, without masking of the trial names. We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gurusamy 2009b; Gluud 2013). Due to the risk of biased overestimation of intervention effects in randomised trials with high risk of bias (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), we assessed the following domains of risk of bias in the trials.

Sequence generation

• Low risk of bias (the methods used was either adequate (eg, computer‐generated random numbers, table of random numbers) or unlikely to introduce confounding).

• Uncertain risk of bias (there was insufficient information to assess whether the method used was likely to introduce confounding).

• High risk of bias (the method used (eg, quasi‐randomised studies) was improper and likely to introduce confounding).

Allocation concealment

• Low risk of bias (the method used (eg, central allocation) was unlikely to induce bias on the final observed effect).

• Uncertain risk of bias (there was insufficient information to assess whether the method used was likely to induce bias on the estimate of effect).

• High risk of bias (the method used (eg, open random allocation schedule) was likely to induce bias on the final observed effect).

Blinding of participants, personnel, and outcome assessors

• Low risk of bias (blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding).

• Uncertain risk of bias (there was insufficient information to assess whether the type of blinding used was likely to induce bias on the estimate of effect).

• High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement was likely to be influenced by lack of blinding).

Incomplete outcome data

• Low risk of bias (the underlying reasons for missingness were unlikely to make treatment effects departure from plausible values, or proper methods were employed to handle missing data).

• Uncertain risk of bias (there was insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data was likely to induce bias on the estimate of effect).

• High risk of bias (the crude estimate of effects (eg, complete case estimate) was clearly biased due to the underlying reasons for missingness, and the methods used to handle missing data were unsatisfactory).

Selective outcome reporting

• Low risk of bias (the trial protocol was available and all of the trial's pre‐specified outcomes that are of interest in the review had been reported or similar; if the trial protocol was not available, mortality and morbidity were reported).

• Uncertain risk of bias (there was insufficient information to assess whether the magnitude and direction of the observed effect was related to selective outcome reporting).

• High risk of bias (not all of the trial's pre‐specified primary outcomes had been reported or similar).

Vested interest bias

• Low risk of bias (the trial was not performed or supported by any parties that might have conflicting interest, eg, drug manufacturer).

• Uncertain risk of bias (any conflicts of interest of the trialist or trial funder were not clear).

• High risk of bias (the trial was performed or supported by any parties that might have conflicting interest, eg, drug manufacturer).

We classified trials at low risk of bias in all domains to be at low risk of bias.

Measures of treatment effect

We performed the meta‐analyses according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013), using the software package Review Manager 5 (RevMan 2012). For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence intervals (CI) in the presence of two or more trials for the outcomes. In the presence of only one trial for the outcome, we performed the Fisher's exact test using the statistical software StatsDirect 2.7. For continuous variables, we calculated the mean difference (MD) with 95% CI. For count data, outcomes such as serious adverse events, we calculated the rate ratio (RaR) with 95% CI using the methods shown in Section 9.4.8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For such a calculation, one needs the time that the patients were exposed to the risk of serious adverse events in each of the groups. We considered that both groups were exposed to the risk of serious adverse events for the same time period, which is a reasonable assumption considering that the patients were followed up for the same time in both groups. For time‐to‐event outcomes, we calculated the hazard ratio with 95% CI.

Unit of analysis issues

The units of analysis were the patients who had undergone liver transplantation and had developed recurrent hepatitis C virus infection.

Dealing with missing data

We performed the analysis using an intention‐to‐treat basis whenever possible (Newell 1992). Otherwise, we performed an available case analysis (Higgins 2011). In the absence of summary information such as mean and standard deviation for continuous outcomes, we planned to use the median for the meta‐analysis when the mean was not available and impute the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). If it was not possible to calculate the standard deviation from the P value or the CIs, we planned to impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for calculation of MDs and bias the effect estimate to no effect in case of standardised mean difference (Higgins 2011). For time‐to‐event outcomes, we planned to calculate the natural logarithm of the hazard ratio and its standard error using methods suggested by Parmar et al (Parmar 1998).

Assessment of heterogeneity

We explored heterogeneity using the Chi² test with significance set at P value 0.10, and we measured the quantity of heterogeneity using the I² statistic (Higgins 2002). We also used overlapping of CI values on the forest plot to determine heterogeneity.

Assessment of reporting biases

We planned to use visual asymmetry on a funnel plot to explore reporting bias if 10 or more trials were identified (Egger 1997; Macaskill 2001). We also planned to perform the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry.

Data synthesis

We performed the meta‐analyses using the software package Review Manager 5 (RevMan 2012), and following the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). We used both random‐effects model (DerSimonian 1986), and fixed‐effect model (DeMets 1987), meta‐analyses. In case of discrepancy between the two models resulting in change of conclusions, we have reported both results; otherwise we have reported the results of the fixed‐effect model.

Trial sequential analysis

We planned to use trial sequential analysis to control for random errors due to sparse data and repetitive testing of the accumulating data for the primary outcomes (CTU 2011; Thorlund 2011). We planned to add the trials according to the year of publication, and if more than one trial was published in a year, add the trials in alphabetical order according to the surname of the first author. We planned to construct the trial sequential monitoring boundaries on the basis of the required information size (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).   

We planned to apply trial sequential analysis (CTU 2011; Thorlund 2011), using a required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control group proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes when there were at least two trials to determine whether more trials are necessary on this topic (if the trial sequential alpha‐spending monitoring boundary and the required information size is reached or the futility zone is crossed, then more trials are unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). We did not plan to perform trial sequential analysis for quality of life since trial sequential analysis cannot be performed for standardised mean differences.

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses:

• Trials with low risk of bias compared to trials with high risk of bias.

• Adult compared to paediatric liver transplantation.

• Different genotypes of virus.

• Less than six months after liver transplant compared to more than six months after liver transplant.

These subgroup analysis were not performed because of the lack of trials of low risk of bias and because of the few trials included under each outcome.

Sensitivity analysis

We planned to perform a sensitivity analysis excluding the trials in which mean or standard deviation or both were imputed from the analysis.

Results

Description of studies

We identified 2411 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (255 references), MEDLINE (536 references), EMBASE (820 references), and Science Citation Index Expanded (800 references). We excluded 629 duplicates and 1719 clearly irrelevant references through reading abstracts. Sixty‐three references were retrieved for further assessment. We identified two references through scanning reference lists of the identified randomised trials (Kizilisik 1997; Ghalib 2000). We excluded 28 references (25 studies) for the reasons listed in the Characteristics of excluded studies table. Seventeen randomised trials described in 37 references fulfilled the inclusion criteria. Of the 17 trials, only 11 trials could provide data for the review (Gane 1998; Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Angelico 2007; Carrion 2007; Nair 2008; Gane 2009; Belli 2012; Calmus 2012). The reference flow is shown in Figure 1. Details about the sample size, patient characteristics, inclusion and exclusion criteria used in the trials, details of intervention and control, duration of treatment, and the risk of bias in the trials are shown in the Characteristics of included studies table.

1.

Study flow diagram.

Participants

A total of 736 liver transplant recipients with confirmed hepatitis C recurrence were randomised to various experimental interventions versus control interventions. The number of participants in each trial ranged from 5 to 78. A total of 37 participants were excluded from the trial after randomisation for various reasons as shown in the Characteristics of included studies table. The post‐randomisation drop‐outs ranged from 0% to 40%. We were unable to obtain the percentage of females and the mean age of participants in six trials (Crippin 1996; Ghalib 2000; Gordon 2005; Lodato 2008; Gane 2009; Aguilera 2011). The mean age of participants ranged between 51 and 60 years in the remaining trials. The proportion of females in these trials ranged between 11.1% and 37.0%. Eleven trials reported the proportion of patients belonging to viral genotype I (a subtype that is more difficult to treat than other subtypes) (Gane 1998; Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Ghalib 2006; Angelico 2007; Carrion 2007; Lodato 2008; Yedibela 2011; Calmus 2012). The proportion of genotype I patients ranged between 50% and 100%. One trial included patients at least three months after liver transplantation (Crippin 1996). Ten trials included patients at least six months after liver transplantation (Gane 1998; Cotler 2001; Samuel 2003; Chalasani 2005; Angelico 2007; Carrion 2007; Gane 2009; Yedibela 2011; Belli 2012; Calmus 2012). The remaining six trials did not mention the minimum interval between the liver transplantation and the experimental intervention (Ghalib 2000; Gordon 2005; Ghalib 2006; Lodato 2008; Nair 2008; Aguilera 2011). Eleven trials included only patients with histological evidence of chronic viral hepatitis in the liver graft (Crippin 1996; Gane 1998; Samuel 2003; Chalasani 2005; Ghalib 2006; Angelico 2007; Carrion 2007; Lodato 2008; Nair 2008; Aguilera 2011; Belli 2012; Calmus 2012). Overall, we included 501 patients in 11 trials in the various comparisons in this systematic review (Gane 1998; Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Angelico 2007; Carrion 2007; Nair 2008; Gane 2009; Belli 2012; Calmus 2012).

Comparisons

The trials included the following 13 comparisons. We chose the experimental intervention as the group that required an additional drug or a higher dosage (or both). We also considered 48 to 52 weeks as the standard duration of treatment and if there was a longer duration or shorter duration we considered that as the experimental intervention.

1. Pegylated (peg) interferon versus no intervention control (Chalasani 2005) ‐ 67 participants randomised to peg interferon (n = 32) versus no intervention control (n = 33) (two post‐randomisation drop‐outs).

2. Peg interferon plus ribavirin versus no intervention control (Carrion 2007; Belli 2012) ‐ 127 participants randomised to intervention (n = 63) versus no intervention control (n = 63) (one post‐randomisation drop‐out).

3. Ribavirin plus peg interferon versus peg interferon (Angelico 2007; Gane 2009) ‐ 98 participants randomised to Ribavirin plus peg interferon (n = 49) versus peg interferon control (n = 49).

4. Peg interferon (1.5 μg/kg/week; high dose) plus ribavirin versus peg interferon (0.5 μg/kg/week; low dose) plus ribavirin (Gordon 2005; Ghalib 2006) ‐ 72 participants randomised to high‐dose intervention (n = 41) versus low‐dose intervention control (n = 31).

5. Peg interferon alpha 2a versus peg interferon alpha 2b (Aguilera 2011) ‐ 68 participants randomised to peg interferon alpha 2a (n = 34) versus peg interferon alpha 2b (n = 34).

6. Amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin (Nair 2008) ‐ 50 participants randomised to amantadine plus peg interferon plus ribavirin (n = 13) versus peg interferon plus ribavirin (n = 17) (20 post‐randomisation drop‐outs).

7. Interferon versus no intervention control (Crippin 1996; Cotler 2001) ‐ 47 participants randomised to interferon (n = 27) versus no intervention control (n = 13) (eight post‐randomisation drop‐outs).

8. Interferon plus ribavirin versus no intervention control (Samuel 2003) ‐ 52 participants randomised to interferon plus ribavirin (n = 28) versus no intervention control (n = 24).

9. Interferon plus ribavirin for 24 weeks versus interferon plus ribavirin for 48 weeks (Ghalib 2000) ‐ 5 participants randomised to short‐course experimental intervention (n = 3) versus standard course control (n = 2).

10. Ribavirin versus interferon (Gane 1998) ‐ 30 participants randomised to ribavirin (n = 40) versus interferon (n = 37) (one post‐randomisation drop‐out).

11. Ribavirin versus placebo (Calmus 2012) ‐ 78 participants randomised to ribavirin (n = 14) versus placebo control (n = 14) (two post‐randomisation drop‐outs).

12. Peg interferon plus ribavirin versus no intervention control in non‐responders (Lodato 2008) ‐ 18 participants who did not have virological response at 24 weeks of peg interferon plus ribavirin (non‐responders) were randomised to continued intervention (n = 9) versus no intervention (n = 9).

13. Ribavirin plus peg interferon versus peg interferon in relapsers and non‐responders to interferon and ribavirin therapy (Yedibela 2011) ‐ 24 participants randomised to Ribavirin plus peg interferon (n = 10) and versus peg interferon control (n = 11) (three post‐randomisation drop‐outs).

Peg interferon alpha 2a was used in four trials (Chalasani 2005; Angelico 2007; Gane 2009; Aguilera 2011), and peg interferon alpha 2b was used in seven trials (Gordon 2005; Ghalib 2006; Carrion 2007; Lodato 2008; Nair 2008; Aguilera 2011; Belli 2012). Interferon alpha 2a was used in two trials (Crippin 1996; Cotler 2001), and interferon alpha 2b was used in two trials (Ghalib 2000; Samuel 2003). One trial used pegylated interferon (Yedibela 2011). No details regarding whether this was alpha 2a or alpha 2b was stated in this trial (Yedibela 2011). One trial used interferon alpha (Gane 1998). No details regarding whether this was 2a or 2b were reported in this trial (Gane 1998).

Outcome measures

The outcomes reported in the trials were mortality (Gane 1998; Cotler 2001; Samuel 2003; Chalasani 2005; Angelico 2007; Carrion 2007; Gane 2009; Calmus 2012), retransplantation (Cotler 2001; Calmus 2012), serious adverse events (Chalasani 2005; Angelico 2007; Gane 2009; Calmus 2012), graft rejections after starting treatment (Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Angelico 2007; Carrion 2007; Gane 2009; Belli 2012), and worsening of fibrosis (Gane 1998; Samuel 2003; Chalasani 2005; Angelico 2007; Carrion 2007; Nair 2008; Belli 2012). None of the trials reported quality of life or liver decompensation. Six trials did not report any outcomes of interest and so did not provide any data for the review (Crippin 1996; Ghalib 2000; Ghalib 2006; Lodato 2008; Aguilera 2011; Yedibela 2011). The other outcome measures reported by the individual trials are shown in the Characteristics of included studies table.

Risk of bias in included studies

The risk of bias is summarised in the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3). Eleven trials had adequate generation of allocation sequence (Crippin 1996; Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Ghalib 2006; Angelico 2007; Carrion 2007; Lodato 2008; Belli 2012; Calmus 2012). Five trials had adequate allocation concealment (Cotler 2001; Samuel 2003; Chalasani 2005; Gordon 2005; Ghalib 2006; Belli 2012; Calmus 2012). Blinding of participants and healthcare providers is very difficult and may even be considered unethical by some in trials in which interferon or peg interferon was used in only one arm (Crippin 1996; Ghalib 2000; Cotler 2001; Samuel 2003; Chalasani 2005; Carrion 2007; Lodato 2008; Belli 2012), as the interferon had to be given subcutaneously weekly (peg interferon) or three time weekly (interferon). Understandably, no placebo was used in these trials. However, there is a potential bias in the effect estimate because of lack of blinding. In the remaining trials, a placebo could be used to blind the participants and healthcare providers/outcome assessors (Gane 1998; Gordon 2005; Ghalib 2006; Angelico 2007; Nair 2008; Gane 2009; Aguilera 2011; Yedibela 2011; Calmus 2012). However, only one of these nine trials used placebo (Calmus 2012), and the blinding was inadequate in the remaining eight trials (Gane 1998; Gordon 2005; Ghalib 2006; Angelico 2007; Nair 2008; Gane 2009; Aguilera 2011; Yedibela 2011). Seven trials were free from bias due to incomplete outcome data (Cotler 2001; Samuel 2003; Gordon 2005; Ghalib 2006; Angelico 2007; Carrion 2007; Lodato 2008). Only two trials reported both mortality and liver transplantation and were considered to be at low risk of selective reporting bias (Cotler 2001; Calmus 2012). The protocol was not available for any of the trials. Thus, all the trials were considered to be at risk of bias due to selective outcome reporting. None of the trials were free from source of funding bias. All the trials were considered to be of high risk of bias.

2.

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

3.

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

Effects of interventions

See: Table 1; Table 2

Mortality

The following comparisons reported mortality (Analysis 1.1). The trials that contributed to the comparisons are shown along with the number of participants, RR, and P value (derived from the Fisher's exact test when there was only one trial and derived from Review Manager (RevMan 2012) when there were two or more trials). We have summarised the findings in Table 1.

1.1. Analysis.

Comparison 1 Intervention versus control, Outcome 1 Mortality.

1. Peg interferon versus no intervention control (Chalasani 2005; 65 participants): RR 0.48; 95% CI 0.05 to 5.09; Fisher's exact test P value = 0.61.

2. Peg interferon plus ribavirin versus no intervention control (Carrion 2007; 54 participants): RR 3.00; 95% CI 0.13 to 70.53; Fisher's exact test P value = 1.00.

3. Ribavirin plus peg interferon versus peg interferon (Angelico 2007; Gane 2009; 98 participants): RR 0.50; 95% CI 0.05 to 5.20; test for overall effect P value = 0.56.

4. Interferon versus no intervention control (Cotler 2001; 12 participants): RR 1.67; 95% CI 0.08 to 33.75; Fisher's exact test P value = 1.00.

5. Interferon plus ribavirin versus no intervention control (Samuel 2003; 52 participants): RR 0.29; 95% CI 0.01 to 6.74; Fisher's exact test P value = 0.46.

6. Ribavirin versus interferon (Gane 1998; 30 participants): RR not estimable; Fisher's exact test P value = 1.00.

7. Ribavirin versus placebo (Calmus 2012; 77 participants): RR not estimable; Fisher's exact test P value = 1.00.

Overall, there was no significant difference in mortality between the intervention and control groups in any of the comparisons. There was no change in results when using the random‐effects model for the ribavirin plus peg interferon versus peg interferon comparison, the only comparison with at least two trials. The issue of random‐effects model versus fixed‐effect model did not arise in the other comparisons because of the presence of only one trial in these comparisons.

Trial sequential analysis was performed for the only comparison with at least two trials (ie, ribavirin plus peg interferon versus peg interferon). The proportion of patients recruited was less than 1% of the diversity‐adjusted required information size (DARIS) and so the trial sequential monitoring boundaries were not drawn. The conventional boundaries were not crossed (Figure 4.

4.

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

Retransplantation

Two comparisons reported retransplantation (Analysis 1.2). The trials that contributed to the comparisons are shown along with the number of participants, RR, and P value derived from the Fisher's exact test as there was only one trial for each comparison. We have summarised the findings in Table 2.

1.2. Analysis.

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

1. Interferon versus no intervention control (Cotler 2001; 12 participants): RR 1.67; 95% CI 0.08 to 33.75; Fisher's exact test P value = 1.00.

2. Ribavirin versus placebo (Calmus 2012; 77 participants): RR not estimable; Fisher's exact test P value = 1.00.

Overall, there was no significant difference in retransplantation between the intervention and control groups in the two comparisons. The issue of random‐effects model versus fixed‐effect model did not arise in the two comparisons because of the presence of only one trial in the two comparisons. Trial sequential analysis was not performed as there was only one trial for each comparison.

Quality of life

Quality of life was not reported in any of the trials.

Serious adverse events

Two comparisons reported the proportion of participants who developed serious adverse events (Analysis 1.3). The trials that contributed to the comparisons are shown along with the number of participants, RR, and P value derived from Fisher's exact test as there was only one trial for each comparison.

1.3. Analysis.

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

1. Ribavirin plus peg interferon versus peg interferon (Gane 2009; 56 participants): RR 3.40; 95% CI 1.46 to 7.94; Fisher's exact test P value = 0.002.

2. Ribavirin versus placebo (Calmus 2012; 77 participants): RR 5.55; 95% CI 0.70 to 43.95; Fisher's exact test P value = 0.11.

Overall, there was a significantly higher proportion of participants who developed serious adverse events in the ribavirin plus peg interferon combination therapy than peg interferon monotherapy and no significant difference in the proportion of participants who developed serious adverse events between the ribavirin and placebo groups as shown above. The issue of random‐effects model versus fixed‐effect model did not arise in the two comparisons because of the presence of only one trial in each of the two comparisons. Trial sequential analysis was not performed as there was only one trial for each comparison.

Two comparisons reported the number of serious adverse events in each group (Analysis 1.4). The trials that contributed to the comparisons are shown along with the number of participants, RaR, and P value derived from Review Manager (RevMan 2012).

1.4. Analysis.

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

1. Peg interferon versus no intervention control (Chalasani 2005; 65 participants): RaR 1.15; 95% CI 0.52 to 2.57; P value = 0.73.

2. Ribavirin plus peg interferon versus peg interferon (Angelico 2007; 42 participants): RaR 1.20; 95% CI 0.36 to 3.96; P value = 0.56.

Overall, there was no significant difference in number of serious adverse events between the intervention and control groups in the two comparisons. The issue of random‐effects model versus fixed‐effect model did not arise in the two comparisons because of the presence of only one trial in each of the two comparisons.

Liver decompensation

Liver decompensation was not reported in any of the trials.

Graft rejections

The following two comparisons reported graft rejections requiring retransplantation (Analysis 1.5). The trials that contributed to the comparisons are shown along with the number of participants, RR, and P value (derived from Fisher's exact test as there was only one trial for each comparison).

1.5. Analysis.

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

1. Peg interferon plus ribavirin versus no intervention control (Belli 2012; 72 participants): (RR 1.00; 95% CI 0.07 to 15.38); Fisher's exact test P value = 1.00.

2. Interferon versus no intervention control (Cotler 2001; 12 participants): RR 1.67; 95% CI 0.08 to 33.75; Fisher's exact test P value = 1.00.

Only one comparison reported graft rejections requiring medical treatment (Analysis 1.6). The trial that contributed to the comparison is shown along with the number of participants, RR, and P value (derived from Fisher's exact test as there was only one trial for each comparison).

1.6. Analysis.

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

1. Ribavirin plus peg interferon versus peg interferon (Angelico 2007; 42 participants): RR 0.33; 95% CI 0.04 to 2.95; Fisher's exact test P value = 0.061.

The following comparisons reported graft rejections without describing the treatment that these participants underwent for graft rejection (Analysis 1.7). The trials that contributed to the comparisons are shown along with the number of participants, RR, and P value (derived from Fisher's exact test when there was only one trial and derived from Review Manager when there were two or more trials) (RevMan 2012).

1.7. Analysis.

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

1. Peg interferon versus control (Chalasani 2005; 65 participants): RR 24.26; 95% CI 1.50 to 393.41; Fisher's exact test P value = 0.0001.

2. Peg interferon plus ribavirin versus control (Carrion 2007; 54 participants): RR 3.00; 95% CI 0.13 to 70.53; Fisher's exact test P value = 1.00.

3. Ribavirin plus peg interferon versus peg interferon (Gane 2009; 56 participants): RR 1.00; 95% CI 0.07 to 15.21; Fisher's exact test P value = 1.00.

4. Peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin (Gordon 2005; 13 participants): RR not estimable; Fisher's exact test P value = 1.00.

5. Interferon plus ribavirin versus control (Samuel 2003; 52 participants): RR 2.59; 95% CI 0.11 to 60.69; Fisher's exact test P value = 1.00.

Overall there was no significant difference in the proportion of participants who developed graft rejection in any of the comparisons other than peg interferon versus control. In the comparison between peg interferon and control, the proportion of participants who developed graft rejection (of unknown treatment) was significantly higher in the peg interferon group than the control group as shown above. The issue of random‐effects model versus fixed‐effect model did not arise in any of these comparisons because of the presence of only one trial in these comparisons. Trial sequential analysis was not performed as there was only one trial for each comparison.

Fibrosis worsening

The following comparisons reported worsening of fibrosis (Analysis 1.8). The trials that contributed to the comparisons are shown along with the method used to measure the fibrosis, time of follow‐up measurement of fibrosis, number of participants, RR, and P value (derived from Fisher's exact test when there was only one trial and derived from Review Manager when there were two or more trials) (RevMan 2012).

1.8. Analysis.

Comparison 1 Intervention versus control, Outcome 8 Fibrosis worsening.

1. Peg interferon versus no intervention control (Chalasani 2005; Ishak score, at the end of treatment; 45 participants): RR 0.82; 95% CI 0.30 to 2.19; Fisher's exact test P value = 0.75.

2. Peg interferon plus ribavirin versus no intervention control (Carrion 2007; Belli 2012; Sheur classification, six months after end of treatment (Carrion 2007) and Ishak score,12 months after end of treatment (Belli 2012); 126 participants): Fixed‐effect model = RR 0.71; 95% CI 0.51 to 0.98; test for overall effect P value = 0.04; random‐effects model = RR 0.63; 95% CI 0.23 to 1.74; test for overall effect P value = 0.38.

3. Ribavirin plus peg interferon versus peg interferon (Angelico 2007; Ishak score, 6 to 12 months after end of treatment; 42 participants): RR 2.00; 95% CI 0.20 to 20.41; Fisher's exact test P value = 1.00.

4. Amantadine plus peg interferon plus ribavirin versus peg interferon versus ribavirin (Nair 2008; METAVIR score, at the end of treatment; 30 participants): RR 0.75; 95% CI 0.28 to 2.02; Fisher's exact test P value = 0.71.

5. Interferon plus ribavirin versus no intervention control (Samuel 2003; METAVIR score, 24 weeks after end of treatment; 52 participants): RR 0.29; 95% CI 0.01 to 6.74; Fisher's exact test P value = 0.46.

6. Ribavirin versus interferon (Gane 1998; Knodell score, 24 weeks from start of treatment; 30 participants): RR 0.73; 95% CI 0.28 to 1.88; Fisher's exact test P value = 0.71.

Overall, there was no significant difference in fibrosis worsening between the intervention and control groups in any of the comparisons except for the fixed‐effect model for the comparison peg interferon plus ribavirin versus no intervention control, which showed significantly lower fibrosis worsening in the peg interferon plus ribavirin group as shown above. However, on using the random‐effects model, there was no significant difference between these groups as shown above. The issue of random‐effects model versus fixed‐effect model did not arise in the other comparisons because of the presence of only one trial in each of these comparisons. Trial sequential analysis was performed for the only comparison with at least two trials (ie, ribavirin plus peg interferon versus no intervention control). The proportion of patients recruited was only 3.1% of the DARIS and so trial sequential boundaries were not drawn. The conventional boundaries were not crossed (Figure 5).

5.

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

Subgroup analysis

We did not perform any subgroup analyses because of the few trials included under each comparison.

Sensitivity analysis

Quality of life was not reported in any of the trials. So, we did not impute mean or standard deviation in any of the trials. For this reason, we did not perform any sensitivity analyses.

Reporting bias

We did not explore reporting bias using a funnel plot because of the few trials included under each comparison.

Discussion

This review has assessed the various therapies for hepatitis C virus recurrence in participants with liver transplantation. There were no significant differences in the mortality, retransplantation, or graft rejection requiring treatment in any comparison in the few trials that reported these outcomes. Quality of life and hepatic decompensation were not reported in any of the trials. The proportion of patients with serious adverse events was significantly higher in the ribavirin plus peg interferon combination therapy than peg interferon monotherapy. There was no significant difference in the proportion of patients who developed serious adverse events and the number of serious adverse events in the other comparisons in which serious adverse events were reported. These are the main clinical outcomes, which should determine whether antiviral therapy should be used for the treatment of recurrent liver graft infection with hepatitis C virus. However, the participants were followed up for only 24 to 26 weeks after the end of treatment (ie, around 17 to 18 months). Longer periods of follow‐up are necessary to determine any clinical benefit.

Anaemia, renal impairment, and other adverse effects (such as thrombocytopenia, neutropenia, headache, insomnia, and myalgia) are frequent with antiviral treatment (Gurusamy 2010). Considering the lack of clinical benefit and the frequent adverse effects, there is currently no evidence to recommend antiviral treatment for recurrent liver graft infection with hepatitis C virus. Having achieved the main objective, we decided to analyse the various factors that should be taken into account if a new trial assessing the role of antiviral treatment for recurrent liver graft infection with hepatitis C virus is performed.

One of the important issues that should be considered before a trial assessing the role of antiviral therapy for recurrent liver graft infection with hepatitis C virus is performed is the safety of the treatment. As mentioned previously, adverse effects such as thrombocytopenia, neutropenia, or anaemia may require reduction in dose or cessation of therapy. Evidence from a randomised clinical trial showed that granulocyte colony‐stimulating‐factor is effective in normalising neutropenia induced by interferon plus ribavirin therapy in participants with chronic viral hepatitis (Sharvadze 2007). Evidence from three randomised clinical trials showed that epoetin alpha (recombinant erythropoietin) is effective in 83% to 100% of participants (with chronic hepatitis C virus infection on interferon plus ribavirin therapy) in avoiding a reduction in ribavirin dose because of anaemia (Dieterich 2003; Afdhal 2004; Sharvadze 2006). Use of granulocyte colony‐stimulating‐factor and erythropoietin may help in achieving higher cumulative doses in participants with hepatitis C virus recurrence after liver transplantation also. Multivariate analysis of case series of interferon plus ribavirin therapy in liver transplantation participants showed that the participants who attained sustained virological response (SVR) had greater cumulative doses of interferon and ribavirin than those who did not attain sustained viral response (Sharma 2007). No serious adverse effects that preclude the use of antiviral therapy were reported in any trial. There was a significant difference in the proportion of participants who achieved SVR after combination therapy with peg interferon plus ribavirin when compared with no treatment (see comparison number 2 above). Observational studies have shown that SVR after treatment is associated with reduction in mortality (Picciotto 2007) compared with treatment failures. While this could be because of SVR after treatment being a prognostic marker, there is also a possibility of survival benefit (by decreasing the exposure of the liver to the viral insult) if SVR was achieved. Thus, perhaps it is worth carrying out further trials of low‐bias risk assessing the role of antiviral treatment for recurrent liver graft infection with hepatitis C virus. The main outcomes that need to be assessed in such trials would be mortality, retransplantation (particularly for graft failure), liver decompensation, and quality of life (to determine if the treatment improves the quality adjusted life years and to perform economic evaluation). In order to determine any difference in these outcomes, the duration and method of follow‐up should be appropriate. It is expected that any difference in survival is likely to be noted only after five years. Thus, the trial should be adequately powered; it should use the appropriate methodology and outcomes; and it should include a long period of follow‐up to determine the important outcomes.

The conductors of such trials are likely to face many problems. The first issue is the duration of the hepatitis C virus recurrence. The participants may have different stages of fibrosis in the graft. The effectiveness of the intervention may vary with the stage of fibrosis in the graft. So, the participants have to be stratified based on the stage of the fibrosis and a subgroup analysis based on the stage of fibrosis should be performed. Stratification may also have to be carried out for patient and viral factors such as genotype and the initial viral load, which may also influence the outcomes. The second issue is the choice of the experimental drug. From the trials included in this review, it appears that the combination therapy with peg interferon plus ribavirin (with the use of growth factors if necessary) offers maximum promise. However, considering the duration of recruitment (see below) and the long follow‐up required for the main outcomes to be assessed, it is possible that a much superior treatment becomes available. Protocols should be in place for such an eventuality. The third issue is that of blinding the participants. Since the duration of treatment is 48 to 52 weeks and weekly injections are required for peg interferon, the blinding of the participants may be difficult. This lack of blinding will result in bias in the quality of life measures. However, the main outcomes such as mortality, retransplantation, or liver decompensation may not be affected by lack of patient blinding. The healthcare provider can be blinded by requesting the patient or a third party not involved in the trial to give the subcutaneous injections. The outcome assessors can be blinded if adequate efforts are made to achieve this. Another issue is the bias arising due to missing outcomes. Because of the long duration of follow‐up required for the assessment of outcomes, adequate efforts must be made to minimise the proportion of participants lost to follow‐up. Another important issue is sample size calculations. In a study based on 11,036 liver transplant recipients in the United Network for Organ Sharing (UNOS) Scientific Registry (a database of liver transplant recipients in the USA) with a mean follow‐up of 2.1 years, the actuarial five‐year survival rate was 69.9% in liver transplants performed for hepatitis C virus infection as compared with that in non‐hepatitis C virus participants, which was 76.6% (Forman 2002). The actuarial five‐year graft survival rate was 56.8% in liver transplants performed for hepatitis C virus infections versus 67.7% in liver transplants performed for non‐hepatitis C virus participants. In another retrospective study (Ghobrial 1999), the five‐year retransplantation proportion was 76/374 (20.3%) after a median follow‐up of 22.7 months. The retransplantation proportion directly related to hepatitis C virus recurrence was 3.4%. However, retransplantation rate may be a difficult outcome as there is no uniform agreement among experts regarding the criteria for retransplantation and may not be a suitable objective outcome measure. If survival is chosen as the primary outcome, the presence of hepatocellular carcinoma in the removed liver may be a confounding factor (if a significant proportion of the participants have hepatocellular carcinoma). This may necessitate two different trials or one trial with a planned subgroup analysis of participants with and without hepatocellular carcinoma. This is because of the significantly lower survival rate in participants undergoing liver transplantation for malignancy (Forman 2002). The proportion of participants undergoing liver transplantation for malignancy who had hepatocellular carcinoma is not clear from the report by Forman 2002. However, the presence of hepatocellular carcinoma prior to liver transplantation for hepatitis C may influence the survival necessitating two different trials or one trial with a planned subgroup analysis.

None of the trials reported whether the donors consented for organ donation. Future trials should clearly state whether donors consented for organ donation.

Authors' conclusions

Implications for practice.

Considering the lack of clinical benefit, there is currently no evidence to recommend or refute antiviral treatment for participants with recurrent liver graft infection with hepatitis C virus.

Implications for research.

Further randomised clinical trials are necessary to evaluate optimal treatment of participants having recurrent hepatitis C virus infection after liver transplantation. Such trials must also include a no intervention control group (untreated group) to determine if treatment provides any benefit.

The main outcomes that need to be assessed in such a trial would be mortality, retransplantation (particularly for graft failure), liver decompensation, and quality of life (to determine if the treatment improves the quality adjusted life years and to perform economic evaluation).

Future trials need to be designed according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (SPIRIT 2013; SPIRIT 2013a), and conducted and reported according to the CONSORT (CONsolidated Standards of Reporting Trials) Statement (CONSORT 2009).

What's new

Date	Event	Description
3 September 2014	Amended	A sentence in the plain language summary is now amended: in stead of 'versus' it should have been written 'including', so the correct sentence is: "The patients were randomised to receive different treatments including no treatment in these 11 trials." In the remaining review text, the sentence was correctly written.

History

Protocol first published: Issue 4, 2007
 Review first published: Issue 1, 2009

Date	Event	Description
17 October 2013	Amended	Title change: "Antiviral interventions for liver transplant patients with recurrent graft infection due to hepatitis C virus". The earlier two versions were published with the title: "Antiviral therapy for recurrent liver graft infection with hepatitis C virus".
14 March 2013	Amended	Author order: Kurinchi Selvan Gurusamy, Emmanuel Tsochatzis, Clare D Toon, Elias Xirouchakis, Andrew K Burroughs, Brian R Davidson
13 March 2013	New citation required and conclusions have changed	The methods were updated to the current methods. The conclusions were revised from "Considering the lack of clinical benefit and the frequent adverse effects, there is currently no evidence to recommend antiviral treatment for recurrent liver graft infection with hepatitis C virus. Further randomised clinical trials with adequate trial methodology and adequate duration of follow‐up are necessary" to "Considering the lack of clinical benefit, there is currently no evidence to recommend antiviral treatment for recurrent liver graft infection with hepatitis C virus. Further randomised clinical trials with low risk of bias and random errors with adequate duration of follow‐up are necessary".
14 February 2013	New search has been performed	Searches were updated. Five new trials were included in the analysis (Gane 2009; Yedibela 2011; Aguilera 2011; Calmus 2012; Belli 2012).

Appendices

Appendix 1. Search strategies

Database	Period of Search	Search Strategy
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Wiley)	Issue 1, 2013.	#1 (liver or hepatic) AND (transplant* or graft*) #2 MeSH descriptor Liver Transplantation explode all trees #3 (#1 OR #2) #4 hepatitis C OR "parenterally transmitted hepatitis" OR "parenterally‐transmitted hepatitis" OR "PT‐NANBH" #5 MeSH descriptor Hepatitis C explode all trees #6 (#4 OR #5) #7(#3 AND #6)
MEDLINE (PubMed)	1951 to February 2013.	(((liver or hepatic) AND (transplant* or graft*)) OR "Liver Transplantation"[MeSH]) AND ("Hepatitis C"[MeSH] OR hepatitis C OR "parenterally transmitted hepatitis" OR "parenterally‐transmitted hepatitis" OR "PT‐NANBH") AND (((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp]) NOT (animals [mh] NOT human [mh]))))
EMBASE (OvidSP)	1974 to February 2013.	1 exp CROSSOVER PROCEDURE/ 2 exp DOUBLE BLIND PROCEDURE/ 3 exp SINGLE BLIND PROCEDURE/ 4 exp RANDOMIZED CONTROLLED TRIAL/ 5 (((RANDOM* or FACTORIAL* or CROSSOVER* or CROSS) and OVER*) or PLACEBO* or (DOUBL* and BLIND*) or (SINGL* and BLIND*) or ASSIGN* or ALLOCAT* or VOLUNTEER*).af. 6 1 or 2 or 3 or 4 or 5 7 (liver or hepatic).af. 8 (transplant* or graft*).af. 9 8 and 7 10 exp Liver Transplantation/ 11 10 or 9 12 (hepatitis C or parenterally transmitted hepatitis or parenterally‐transmitted hepatitis or PT‐NANBH).af. 13 exp Hepatitis C/ or exp Hepatitis Virus/ 14 13 or 12 15 6 and 11 and 14
Science Citation Index Expanded (Web of Knowledge)	1970 to February 2013.	#1 TS=((liver or hepatic) AND (transplant* or graft*)) #2 TS=(hepatitis C OR "parenterally transmitted hepatitis" OR "parenterally‐transmitted hepatitis" OR "PT‐NANBH") #3 TS=(random* OR blind* OR placebo* OR meta‐analysis) #4 #3 AND #2 AND #1

Data and analyses

Comparison 1. Intervention versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Peg interferon versus no intervention control	1	65	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 5.09]
1.2 Peg interferon plus ribavirin versus no intervention control	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 70.53]
1.3 Ribavirin plus peg interferon versus peg interferon	2	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.05, 5.20]
1.4 Interferon versus no intervention control	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.08, 33.75]
1.5 Interferon plus ribavirin versus no intervention control	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.01, 6.74]
1.6 Ribavirin versus interferon	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.7 Ribavirin versus placebo	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Retransplantation after start of therapy	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Interferon versus no intervention control	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.08, 33.75]
2.2 Ribavirin versus placebo	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Treatment‐related serious adverse events (proportion)	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 Ribavirin plus peg interferon versus peg interferon	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	3.4 [1.46, 7.94]
3.2 Ribavirin versus placebo	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	5.55 [0.70, 43.95]
4 Treatment‐related serious adverse events (number of serious adverse events)	2		Rate Ratio (Fixed, 95% CI)	Subtotals only
4.1 Peg interferon versus no intervention control	1	65	Rate Ratio (Fixed, 95% CI)	1.15 [0.52, 2.57]
4.2 Ribavirin plus peg interferon versus peg interferon	1	42	Rate Ratio (Fixed, 95% CI)	1.20 [0.36, 3.96]
5 Graft rejection requiring retransplantation after start of therapy	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 Peg interferon plus ribavirin versus no intervention control	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.07, 15.38]
5.2 Interferon versus no intervention control	1	12	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.08, 33.75]
6 Graft rejection requiring medical treatment	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 Ribavirin plus peg interferon versus peg interferon	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 2.95]
7 Graft rejection (others with unknown treatment)	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.1 Peg interferon versus no intervention control	1	65	Risk Ratio (M‐H, Fixed, 95% CI)	24.26 [1.50, 393.41]
7.2 Peg interferon plus ribavirin versus no intervention control	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 70.53]
7.3 Ribavirin plus peg interferon versus peg interferon	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.07, 15.21]
7.4 Peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.5 Interferon plus ribavirin versus no intervention control	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	2.59 [0.11, 60.69]
8 Fibrosis worsening	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.1 Peg interferon versus no intervention control	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.30, 2.19]
8.2 Peg interferon plus ribavirin versus no intervention control	2	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.51, 0.98]
8.3 Ribavirin plus peg interferon versus peg interferon	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 20.41]
8.4 Amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.28, 2.02]
8.5 Interferon plus ribavirin versus no intervention control	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.01, 6.74]
8.6 Ribavirin versus interferon	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.28, 1.88]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aguilera 2011.

Methods	Randomised clinical trial.
Participants	Country: Spain. Number randomised: 68. Post‐randomisation drop‐outs: Not stated. Revised sample size: 68. Mean age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: Established recurrent HCV disease evaluated by a liver biopsy. Exclusion criteria: HIV seropositivity. HBV coinfection. Contraindications for antiviral therapy. Rejection in the baseline biopsy.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon ‐ alpha 2a (n = 34). Further details: Not available. Genotype 1: Not stated. Group 2: Peg interferon ‐ alpha 2b (n = 34). Further details of control: Not available. Genotype 1: Not stated.
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempts were made to contact the authors in March 2013. No replies were received. Consent for 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.

Angelico 2007.

Methods	Randomised clinical trial.
Participants	Country: Italy. Number randomised: 42. Post‐randomisation drop‐out: 0. Revised sample size: 42. Mean age: 57 years. Females: 14 (33.3%). Interval between liver transplantation and start of intervention/control: 48 months for ribavirin plus peg interferon vs. 40 months per interferon. Inclusion criteria: OLT with recurrent HCV. Non‐cirrhotic. Age ≤ 70 years. Liver transplantation due to HCV‐related cirrhosis performed at least 1 year earlier. Detectable serum HCV‐RNA. Persistently abnormal ALT serum levels. Histological evidence of established HCV hepatitis in the graft. Exclusion criteria: Previous antiviral treatment after liver transplantation. Baseline counts of leukocytes < 3000 cells/mm3; platelets < 70,000 cells/mm3; Hb value < 12 g/dL. Serum creatinine > 2 mg/dL at least twice in the last 6 months. Active alcohol or drugs, or both,consumption. HIV virus or HBV co‐infections. Renal or thyroid dysfunctions. History of autoimmune hepatitis, haematological or psychiatric diseases. Significant cardiovascular abnormalities. Neoplastic diseases. Clinically significant bleeding disorders. Other organ transplantation. Pregnancy or lactation. Active steroid treatment.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Ribavirin plus peg interferon (n = 21). Further details: Ribavirin: 200 mg/day to maximum tolerated dose; interferon 180 μg/weekly for 48 weeks. Genotype 1: 18 (85.7%). Group 2: Peg interferon (n = 21). Further details: Peg interferon: 180 μg/weekly for 48 weeks. Genotype 1: 17 (81%).
Outcomes	The outcomes reported were mortality, graft rejection, serious adverse events, and fibrosis response.
Notes	Attempts were made to contact the authors in December 2007. Authors provided additional information. Further attempts were made to contact the authors in February 2013. No replies were received. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Using a computerized random list blinded to clinical investigators" (author replies).
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 retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "They received partial funding from Roche s.p.a., Milan, Italy which enabled them to carry out their research."

Belli 2012.

Methods	Randomised clinical trial
Participants	Country: Multicentre (Europe). Number randomised: 73. Post‐randomisation drop‐outs: 1 (1.4%). Revised sample size: 72. Mean age: 54 years. Females: 8 (11.1%). Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: Adult first liver transplant participants (> 18 years of age). Had mild–moderate histological recurrent hepatitis C. Exclusion criteria: 1. Signs of cholestatic hepatitis (defined by a total bilirubin > 3 mg/dL). 2. Ishak staging score higher than 3 at the time of the 1 year protocol liver biopsy. 3. Previous organ transplantation. 4. Co‐infection with hepatitis or HIV. 5. Ongoing biliary tract disease at the time of randomisation. 6. Major vascular problems portal vein or hepatic artery thrombosis. 7. Renal failure defined by serum creatinine > 2 mg/dL. 8. Contraindications to interferon and ribavirin therapy.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon alpha 2b (n = 36). Further details: Treated participants received escalating doses of peg interferon alpha 2b starting from 0.5‐1 µg/kg once weekly, up to 1.5 µg/kg within 2‐4 weeks if tolerated together with escalating doses of ribavirin starting from 400‐600 mg once daily, up to a maximal tolerated dose of 14 mg/kg/day for 52 weeks. Genotype 1: Not stated. Group 2: Control (n = 36). Further details: No intervention. Genotype 1: Not stated.
Outcomes	The outcomes reported were rejection and fibrosis worsening.
Notes	Attempts were made to contact the authors in March 2013. No replies were received. Reasons for post‐randomisation drop‐outs: Did not receive allocated intervention. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was centralized and performed by an independent unit according to a randomization list prepared by a biostatistician."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was centralized and performed by an independent unit according to a randomization list prepared by a biostatistician."
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "The design of this multicentre, randomized, controlled, open label study was developed …"
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were 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: "Drug supply was provided by Schering‐Plough. A financial support from Schering‐Plough was given to the Co‐ordinating Center and it was utilized for independent monitoring, centralized revision liver biopsies and statistical analysis."

Calmus 2012.

Methods	Randomised clinical trial.
Participants	Country: France. Number randomised: 78. Post‐randomisation drop‐outs: 1 (1.3%). Revised sample size: 77. Mean age: 53 years. Females: 21 (27.3%). Interval between liver transplantation and start of intervention/control: 2.6 years (no data available for each group separately). Inclusion criteria: Adult (age 18‐70 years) first‐time liver transplantation recipients. Recurrent HCV and fibrosis PF1 (METAVIR) at liver biopsy obtained 1‐5 years after liver transplantation. HBsAg‐negative liver disease. Detectable serum HCV RNA by PCR. Must have been taking calcineurin inhibitors (cyclosporine or tacrolimus) with a stable immunosuppressive regimen for at least 6 months. Exclusion criteria: Previous treatment with interferon alpha after transplantation. Retransplantation. Associated organ transplantation. Recurrent hepatocellular carcinoma after liver transplantation. Serum HIV positivity. Acute rejection episode within the past 6 months or histological features compatible with acute or rejection at screening biopsy (ie, acute rejection, loss of > 25% of interlobular bile ducts, centrilobular ischaemia). Fibrosing cholestatic hepatitis. Unresolved biliary complications. Serum creatinine level > 200 µmol/L. GGT level > 20 x ULN. Bilirubin level > 100 µmol/L. Neutrophil count < 1500/mm3. Platelet count < 50,000/mm3. Hb level < 10 g/dL (women) or < 11 g/dL (men).
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Ribavirin (n = 40). Further details: Ribavirin: 1000 mg or function of haematological tolerance for a period of 12 months. Genotype 1: 31 (77.5%). Group 2: Control (n = 37). Further details: Placebo. Genotype 1: 30 (81.1%). Other details: Both groups received 12 months of combination therapy with peg interferon alpha 2a plus ribavirin prior to randomisation.
Outcomes	The outcomes reported were mortality, retransplantation, and serious adverse events.
Notes	Attempts were made to contact the authors in March 2013. Authors provided additional information. Reasons for post‐randomisation drop‐outs: Adverse event. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed on a central basis, with local balance, by questioning an internet site."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed on a central basis, with local balance, by questioning an internet site."
Blinding (performance bias and detection bias) All outcomes	Low risk	Comment: Blinding was achieved by the use of placebo.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were 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: "This work was supported by a grant from the French National Direction for Clinical Research (Direction de la Recherche Clinique) and by Roche Pharma France."

Carrion 2007.

Methods	Randomised clinical trial.
Participants	Country: Spain. Number randomised: 54. Post‐randomisation drop‐out: 0. Revised sample size: 54. Mean age: 60 years. Females: 20 (37%). Interval between liver transplantation and start of intervention/control: 15 months for peg interferon plus ribavirin vs. 17 months for control. Inclusion criteria: Mild hepatitis C recurrence (fibrosis stage F0 to F2). At least 6 months after liver transplantation. 18‐70 years of age. Exclusion criteria: HIV or HBV infection. Previous organ transplantation. Renal failure. Contraindications to interferon and ribavirin treatment.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon plus ribavirin (n = 27). Further details: Peg interferon: 1.5 μg/kg/weekly sc; ribavirin: 400‐1200 mg/day for 48 weeks. Genotype 1: 23 (85.2%). Group 2: Control (n = 27). Further details: No intervention. Genotype 1: 23 (85.2%).
Outcomes	The outcomes reported were mortality, graft rejection, and fibrosis response.
Notes	Attempts were made to contact the authors in March 2009. No replies were received. Consent for donation: Not stated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Allocation of participants was based on computer‐generated random numbers."
Allocation concealment (selection bias)	Unclear risk	Quote: "Allocation concealment was performed with sealed envelopes." Comment: Further details were 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: "Supported in part by grants from Instituto de Salud Carlos III (PI 05/1285, FIS 05/0258). José A. Carrión received a grant from Hospital Clínic (Premi Fi de Residència)."

Chalasani 2005.

Methods	Randomised clinical trial
Participants	Country: USA. Number randomised: 67. Post‐randomisation drop‐out: 2 (3%). Revised sample size: 65. Mean age: 52 years. Females: 10 (15.4%). Interval between liver transplantation and start of intervention/control: 26 months for peg interferon vs. 23 months for control. Inclusion criteria: HCV infected liver transplant recipients. 6 months after liver transplantation. ALT > 1.5 times before randomisation. Histological evidence of hepatitis. No histological evidence of rejection at 8 weeks before randomisation. Exclusion criteria: Prior interferon therapy. Neutrophil 1500/μL; Hb < 10 g/dL. Creatinine > 2.0 mg/dL. Cirrhosis. Cholestatic fibrosing hepatitis. Uncontrolled epilepsy. Alcohol or drug abuse within 1 year of entry. Severe psychiatric illness. Immune disorder. COPD. Cardiac disease. Poorly controlled thyroid disease.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon (n = 33). Further details: Peg interferon: 180 μg/weekly sc for 48 weeks. Genotype 1: 26 (78.8%). Group 2: Control (n = 32). Further details: No intervention. Genotype 1: 24 (75%).
Outcomes	The outcomes reported were mortality, serious adverse events, graft rejection, and fibrosis response.
Notes	Attempts were made to contact the authors in December 2007 and March 2013. Authors provided additional information. Reason for post‐randomisation drop‐outs: 1 did not receive study drug; 1 no investigation beyond baseline investigation. Consent for donation: Not stated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Central randomization generated by the computer" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "Held by third party" (author replies).
Blinding (performance bias and detection bias) All outcomes	High risk	Comment: It was an open‐label study so participants and study personnel were not blinded (author replies).
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 retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "Supported by a grant from Roche Laboratories Inc., Nutley, NJ."

Cotler 2001.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 12. Post‐randomisation drop‐out: Not stated. Revised sample size: 12. Mean age: 54 years. Females: 2 (16.7%). Interval between liver transplantation and start of intervention/control: 34 months for interferon vs. 11 months for control. Inclusion criteria: Adult OLT. > 7 months post transplant. Anti‐HCV seropositive. Persistently detectable HCV RNA in serum after OLT. HCV hepatitis. Exclusion criteria: Cirrhosis. Rejection on histology.
Interventions	Participants were randomly assigned to 1 of 2groups. Group 1: Interferon (n = 8). Further details: Interferon: 3 million units/day for 52 weeks. Genotype 1: 6 (75%). Group 2: Control (n = 4). Further details: no intervention. Genotype 1: 4 (100%).
Outcomes	The outcomes reported were mortality, retransplantation, and graft rejection.
Notes	Attempts were made to contact the authors in December 2007. Authors provided additional information. Further attempts were made to contact the authors in March 2013. No replies were received. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was achieved by a computer generated random number table" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "Held by a third party" (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: "Supported by Roche Laboratories, Inc. and the Byron Koch Memorial Fund."

Crippin 1996.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 35. Post‐randomisation drop‐out: 8 (22.9%). Revised sample size: 27. Average age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: > 3 months post liver transplant. Histological hepatitis. ALT more than 2 times normal. Seropositivity for HCV‐RNA.
Interventions	Participants were randomly assigned to 1 of 4 groups. Group 1: Interferon 1 million units (n = 6). Genotype 1: Not stated. Group 2: Interferon 3 million units (n = 9). Genotype 1: Not stated. Group 3: Interferon 6 million units (n = 6). Genotype 1: Not stated. Group 4: Control (n = 6). Further details: No intervention. Genotype 1: Not stated.
Outcomes	None of the outcomes of interest for this review were reported.
Notes	Attempts were made to contact the authors in December 2007 and March 2013. Authors provided additional information. Reason for post‐randomisation drop‐outs: Not stated. Consent for donation: Not stated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Random number table" (author replies).
Allocation concealment (selection bias)	Unclear risk	Quote: "Sealed envelope" (author replies).
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "Study was not blinded" (author replies).
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.

Gane 1998.

Methods	Randomised clinical trial.
Participants	Country: UK. Number randomised: 30. Post‐randomisation drop‐out: 2 (6.7%). Revised sample size: 28. Mean age: 54 years. Females: 7 (25%). Interval between liver transplantation and start of intervention/ control: 7 months for ribavirin vs. 6 months for interferon. Inclusion criteria: Adults. Surviving at 6 months after OLT‐related HCV cirrhosis. Serological evidence of recurrent HCV infection. Serum AST > normal range. Chronic hepatitis without evidence of rejection. Exclusion criteria: Previous episode of steroid‐resistant acute rejection. Chronic rejection. Pregnant women. Unreliable contraception. WBC < 1500 cells per μl; platelet < 50,000 cells per μl; Hb < 10 g/dL.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Ribavirin (n = 16). Further details: Ribavirin: 500‐600 mg twice daily oral for 24 weeks. Genotype 1: 8 (57.1%). Group 2: Interferon (n = 14). Further details: Interferon: 3 million units three times weekly sc for 24 weeks. Genotype 1: 6 (42.9%).
Outcomes	The outcomes reported were mortality and fibrosis response.
Notes	Attempts were made to contact the authors in December 2007. No replies were received. Reason for post‐randomisation drop‐outs: 2 participants who developed adverse effects from ribavirin group were excluded from analysis. Consent for donation: Not stated. Ethical approval for research was obtained.
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 were 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.

Gane 2009.

Methods	Randomised clinical trial.
Participants	Country: Australia and New Zealand. Number randomised: 56. Post‐randomisation drop‐outs: Not stated. Revised sample size: 56. Mean age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: At least 6 months after liver transplantation (no further details available). Inclusion criteria: Subjects with compensated recurrent hepatitis C after liver transplantation.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon‐alpha 2a plus ribavirin (n = 28). Further details: Peg interferon‐alpha 2a 180 µg/week plus ribavirin 400 mg twice daily for 48 weeks. Genotype 1: Not stated. Group 2: Peginterferon‐alpha 2a (n = 28). Further details: Peginterferon‐alpha 2a monotherapy for 48 weeks. Genotype 1: Not stated.
Outcomes	The outcomes reported were mortality, serious adverse events, and graft rejection.
Notes	Attempts were made to contact the authors in March 2013. No replies were received. Consent for 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 retransplantation were not reported.
Free from source of funding bias?	Unclear risk	Comment: This information was not available.

Ghalib 2000.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 5. Post‐randomisation drop‐out: Not stated. Revised sample size: 5. Mean age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: Adult participants with HCV recurrence after liver transplantation.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Interferon plus ribavirin (n = 3). Further details: Interferon: 6 million units sc three times weekly; ribavirin: 800 mg/day for 24 weeks. Genotype 1: Not stated. Group 2: Interferon plus ribavirin (n = 2). Further details: Interferon: 6 million units sc thrice weekly; ribavirin: 800 mg/day for 48 weeks. Genotype 1: Not stated.
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempts were made to contact the authors in December 2007. No replies were received. Consent for 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.

Ghalib 2006.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 59. Post‐randomisation drop‐out: 0. Revised sample size: 59. Mean age: 51 years. Females: 20 (33.9%). Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: OLT participants with histological recurrent HCV.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon (high dose) plus ribavirin (n = 32). Further details: Interferon: started at 0.5 μg/day for 4 weeks followed by 1.5 μg/day for 48 weeks; ribavirin: 600 mg/day increased to 800 mg/day at 4 weeks. Genotype 1: Not stated individually. Group 2: Peg interferon (low dose) plus ribavirin (n = 27). Further details: Interferon: started at 0.5 μg/day for 52 weeks; ribavirin: 600 mg/day increased to 800 mg/day at 4 weeks. Genotype 1: Not stated individually. Genotype 1 in both groups: 43/59 (72.9%).
Outcomes	None of the outcomes of interest for this review were reported in this review.
Notes	Attempts were made to contact the authors in December 2007. Authors provided additional information. Further attempts were made to contact the authors in March 2013. No replies were received. Consent for donation: Not stated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was by random number table; stratified on genotype and fibrosis stage" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "The random number table was held by the project manager for the study" (author replies).
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "Once the dose was determined for a subject, there was no blinding on dosing of the peginterferon alfa‐2b" (author replies).
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.

Gordon 2005.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 13. Post‐randomisation drop‐out: 0. Revised sample size: 13. Mean age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: 44 months after transplantation (individual groups not stated). Inclusion criteria: Recurrent HCV after liver transplantation.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon (high dose) plus ribavirin (n = 9). Further details: interferon: 1.5 μg/kg/weekly sc; ribavirin 200 mg twice daily increased to 400 mg twice daily for 52 weeks. Genotype 1: 7 (77.8%). Group 2: Peg interferon (low dose) plus ribavirin (n = 4). Further details: interferon: 0.5 μg/kg/weekly sc; ribavirin 200 mg twice daily increased to 400 mg twice daily for 52 weeks. Genotype 1: 2 (50%).
Outcomes	The outcome reported was graft rejection.
Notes	Attempts were made to contact the authors in December 2007. Authors provided additional information. Further attempts were made to contact the authors in March 2013. No replies were received. Consent for donation: Not stated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The envelopes were sealed and mixed by a third party, numbered sequentially from 1‐21, and then opened in sequence at each randomization" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "The envelopes were sealed and mixed by a third party, numbered sequentially from 1‐21, and then opened in sequence at each randomization" (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)	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.

Lodato 2008.

Methods	Randomised clinical trial.
Participants	Country: Italy. Number randomised: 18. Post‐randomisation drop‐out: 0. Revised sample size: 18. Mean age: Not stated. Females: Not stated. Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: Liver transplantation for HCV‐related cirrhosis. Failure to achieve virological response (detectable HCV RNA or < 2 log drop in the HCV RNA level) at week 24 with peg interferon 1 μg/kg weekly plus ribavirin 8‐10 mg/kg/day. Detectable HCV‐RNA by PCR. HCV genotype‐1 infection. Elevated serum ALT levels and histological features of HCV hepatitis in the graft on liver biopsy. Exclusion criteria: Evidence of decompensated liver disease. Histological evidence of rejection and drug‐related injury. HBsAg positivity. HIV positivity. Moderate to severe anaemia (Hb < 10 g/dL). Leukopenia (WBC < 1500 µL). Thrombocytopenia (< 50,000 platelets/μL blood). Impaired renal function (creatinine clearance < 50 mL/minute). Significant history of cardiovascular and psychiatric diseases and ongoing alcohol abuse and previous post‐liver transplantation treatment with peg interferon.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon plus ribavirin (n = 9). Further details: Interferon: 1 μg/kg weekly; ribavirin 8‐10 mg/kg/day for 24 more weeks. Genotype 1: 9 (100%). Group 2: Control (n = 9). Further details: No intervention. Genotype 1: 9 (100%).
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempts were made to contact the authors in April 2009. Authors provided additional information. Further attempts were made to contact the authors in March 2013. No replies were received. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The random sequence was generated by means of random number table" (author replies).
Allocation concealment (selection bias)	Unclear risk	Quote: "The allocation was concealed by means of sealed envelopes" (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)	High risk	Comment: Important outcomes such as mortality and retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "F. Lodato received research funding from Roche S.p.A. M. Biselli and S. Lorenzini received research funding from Associazione per la Ricerca sulle Malattie Epatiche (ARME), Bologna, Italy."

Nair 2008.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 50. Post‐randomisation drop‐out: 20 (40%). Revised sample size: 30. Mean age: 53 years. Females: 8 (23.3%). Interval between liver transplantation and start of intervention/control: 6 months for amantadine plus peg interferon plus ribavirin vs. 6 months for peg interferon plus ribavirin. Inclusion criteria: Positive HCV RNA level by PCR. Elevated ALT. A liver biopsy consistent with recurrent HCV in the absence of acute or chronic rejection. Exclusion criteria: Any cause for active chronic liver disease other than chronic hepatitis C. Evidence of poor graft function or transplant‐related complications such as ascites, high serum bilirubin more than 5 mg/dL, untreated biliary complications such as intrahepatic strictures. Any pre‐existing medical conditions that could interfere with the treatment, such as uncontrolled seizure disorders, ischaemic heart disease, or severe malnutrition. Pre‐existing psychiatric conditions; especially depression, a history of severe psychiatric disorder, such as major psychoses, suicidal ideation, or suicidal attempt. Pre‐existing anaemia Hb < 12 g/dL for women or < 13 g/dL for men. Absolute neutrophil count < 1500/mm3. Platelets < 50,000/mm3. Serum albumin < 3.0 g/dL. Serum creatinine > 1.4 mg/dL.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Amantadine plus peg interferon plus ribavirin (n = 13). Further details: Amantadine: 200 mg/day; interferon: 1.0 μg/kg/week; ribavirin: 800 mg/day for 52 weeks. Genotype 1: Not stated. Group 2: Peg interferon plus ribavirin (n = 17). Further details: Interferon: 1.0 μg/kg/week; ribavirin: 800 mg/day for 52 weeks. Genotype 1: Not stated.
Outcomes	The outcome reported was fibrosis worsening.
Notes	Attempts were made to contact the authors in March 2009. No replies were received. Reason for post‐randomisation drop‐outs: 5 participants who did not receive the drugs because of lack of insurance or because of psychosocial reasons and 15 who developed adverse effects were excluded from analysis. Consent for 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	Quote: "Randomization was done using sealed envelopes with the seal broken only after the patient signed the consent."
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.

Samuel 2003.

Methods	Randomised clinical trial.
Participants	Country: France. Number randomised: 52. Post‐randomisation drop‐out: 0. Revised sample size: 52. Mean age: 57 years. Females: 16 (30.8%). Interval between liver transplantation and start of intervention/control: 54 months for interferon plus ribavirin vs. 57 months for control. Inclusion criteria: Adult first‐time liver transplant recipients. Recurrence of hepatitis C in the graft (> 6 months after transplant). Histopathologically confirmed chronic hepatitis (METAVIR score ≥ 1; Fibrosis score ≥ F0 on liver. 18‐70 years of age. Taking cyclosporine or tacrolimus. Exclusion criteria: Previous treatment with interferon after transplantation. Retransplantation for rejection or chronic hepatitis C on the graft. Associated hepatocellular carcinoma ≥ 3 cm at histological evaluation after transplantation. Serum HBsAg positivity. Serum HIV positivity. Acute rejection episode within the past 6 months or histological features of rejection on screening biopsy. Unresolved biliary complications. Serum creatinine level > 200 μmol/L. GGT level > 20 x ULN. Bilirubin level ≥ 100 μmol/L. Neutrophil count < 1500/mm3; platelet count < 50,000/mm3, Hb level < 10 g/dL for women or < 11 g/dL for men. Associated other organ or bone marrow transplantation. Hepatic arterial thrombosis.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Interferon plus ribavirin (n = 28). Further details: Interferon: 3 million units three times weekly sc; ribavirin: 400‐600 mg twice daily orally for 48 weeks Genotype 1: 23 (82.1%). Group 2: Control (n = 24). Further details: No intervention. Genotype 1: 20 (83.3%).
Outcomes	The outcomes reported was mortality, graft rejection, and fibrosis worsening.
Notes	Attempts were made to contact the authors in December 2007. Authors provided additional information. Further attempts were made to contact the authors in March 2013. No replies were received. Consent for donation: Not stated. Ethical approval for research was obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation was computer generated, by envelope and organized by Schering Plough" (author replies).
Allocation concealment (selection bias)	Low risk	Quote: "The randomisation was computer generated, by envelope and organized by Schering Plough" (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)	High risk	Comment: Important outcomes such as retransplantation were not reported.
Free from source of funding bias?	High risk	Quote: "The randomisation was computer generated, by envelope and organized by Shering Plough."

Yedibela 2011.

Methods	Randomised clinical trial.
Participants	Country: Germany. Number randomised: 24. Post‐randomisation drop‐outs: 3 (12.5%). Revised sample size: 21. Mean age: 52 years. Females: 6 (28.6%). Interval between liver transplantation and start of intervention/control: Not stated. Inclusion criteria: Participants with recurrent HCV after liver transplantation who did not respond or relapsed after initial treatment with interferon (3‐6 million IU three times weekly) plus ribavirin (800‐1200 mg/day) for at least 12 months.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: Peg interferon plus ribavirin (n = 10). Further details: Peg interferon 0.8 µg/kg/week plus ribavirin (800‐1200 mg/day) for 6 months. Genotype 1: 10 (100%). Group 2: Peg interferon (n = 11). Further details: Peg interferon monotherapy 0.8 µg/kg/week for 6 months. Genotype 1: 11 (100%). Both groups received 12 months of combination therapy with peg interferon plus ribavirin prior to randomisation
Outcomes	None of the outcomes of interest for this review were reported in this trial.
Notes	Attempts were made to contact the authors in February 2013. No replies were received. Reasons for post‐randomisation drop‐outs: not completed 6 months of treatment (undergoing treatment). Consent for 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: There were 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.

ALT: alanine transaminase; AST: aspartate aminotransferase; COPD: chronic obstructive pulmonary disease; GGT: gamma‐glutamyltransferase; Hb: haemoglobin; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; OLT: orthotopic liver transplantation; PCR: polymerase chain reaction; peg: pegylated; RNA: ribonucleic acid; sc: subcutaneously; ULN: upper limit of normal; WBC: white blood corpuscle.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Beckebaum 2003	Not a randomised clinical trial.
Beckebaum 2004	Not a randomised clinical trial.
Boillot 1995	Not a randomised clinical trial.
Casanovas 2004	Comment on an included trial.
Castedal 2003	Not a randomised clinical trial.
Catalano 2003	Not a randomised clinical trial.
Ceccherini 2003	Not a randomised clinical trial.
Crippin 2002	Efficacy of treatment before liver transplantation.
Dumortier 2002	Not a randomised clinical trial.
Duvoux 2006	Details on controls not available.
Fontana 2007	Not a randomised clinical trial.
Israeli 2001	Not a randomised clinical trial.
Kizilisik 1997	Not a randomised clinical trial.
Pinna 2001	Not a randomised clinical trial.
Samuel 2002	Review of treatment.
Samuel 2004	Outcomes of interest not reported.
Samuel 2005	Editorial on an included trial.
Samuel 2007	Editorial on an included trial.
Shakil 1999	Outcomes of interest not reported.
Shakil 2004	Outcomes of interest not reported.
Taltavull 2004	Comment on an included trial.
Targhetta 2001	Not a randomised clinical trial.
Testino 2006	Not a randomised clinical trial.
Vargas 1995	Not a randomised clinical trial.
Wietzke 2000	Not a randomised clinical trial.

Differences between protocol and review

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

Differences between first review and update

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

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

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

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

Differences between first update and second update

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

2. We have added trial sequential analysis.

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

Contributions of authors

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

Sources of support

Internal sources

• None, Other.

External sources

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

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

Declarations of interest

None known.

Edited (no change to conclusions)