Summary of findings
Description of the condition
The annual incidence of liver transplantation is 14 per one million population in the UK (NHS UK Transplant), and 21 per one million population in the USA (OPTN/SRTR 2005). Liver transplantation is performed mainly for liver failure arising acutely (called fulminant liver failure, eg, due to viruses, drug overdose), or as a result of chronic decompensated liver disease (eg, cirrhosis due to alcohol consumption, viruses) incompatible with long-term survival. It is also one of the modalities for the management of hepatocellular carcinoma (primary liver cancer) (Lim 2006). The model for end-stage liver disease score (MELD score) has been suggested as one of the methods of determining the severity of end-stage liver failure (Kamath 2001), and is being used as a tool for allocation of livers in some countries (Shiffman 2006). Liver graft can be harvested from living donors (Bombuy 2004), or from cadavers (Koneru 2005; Cescon 2006). Liver transplantation can be performed in adults or in children (Lim 2006). Worldwide, there is a demand for liver donors in surplus of supply. Split liver transplantation (using one cadaveric donor liver for two recipients, ie, an adult and a paediatric recipient) has been suggested as a way to decrease the organ shortage for liver transplant (Corno 2006).
Hepatitis C virus (HCV) cirrhosis is one of the main causes for liver transplantation (Eason 2001). Nearly half of the patients who undergo liver transplantation for HCV cirrhosis have recurrence of HCV in the graft (Jain 2002). Immunosuppressive regimens that avoid steroid use are reported to have a lower rate of graft infection with HCV 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 of HCV is also dependent on hepatitis C subtype, with subtype Ib showing a higher recurrence rate than other subtypes (Sugo 2003); age of donor (Cameron 2006); age of the recipient (Cameron 2006); MELD score of the recipient (Cameron 2006); and warm ischaemic time (Cameron 2006).
Description of the intervention
How the intervention might work
The antiviral agents may decrease the viral load in the liver and decrease the damage to the liver by HCV.
Why it is important to do this review
Antiviral treatments are expensive and associated with significant adverse effects (Gurusamy 2010). It is unclear whether they are of any benefit to the patient. This is an update of the Cochrane review assessing the benefits and harms of the prophylactic peri-transplant antiviral therapy in patients undergoing liver transplantation for chronic HCV infection (Gurusamy 2010).
To compare the benefits and harms of different prophylactic antiviral therapies for patients undergoing liver transplantation for chronic HCV infection.
Criteria for considering studies for this review
Types of studies
We included all randomised clinical trials that assessed antiviral intervention aimed at preventing or reducing the re-infection of graft with HCV (irrespective of language, blinding, publication status, sample size, or whether the trials were adequately powered or not). We excluded quasi-randomised trials and non-randomised studies (where the method of allocating participants to an intervention are not strictly random, eg, date of birth, hospital record number, alternation) for benefits, but we considered them for inclusion for rare and long-term adverse events of treatment.
Types of participants
Patients with hepatitis C viral infection (however defined by authors) who were undergoing or had undergone liver transplantation irrespective of age, cadaveric or living donor, indication for liver transplantation, first or retransplantation, or the immunosuppressive therapy used.
Types of interventions
We included any antiviral prophylactic intervention aimed at preventing or reducing the re-infection with HCV versus no intervention, placebo, or another antiviral prophylactic intervention. We planned to interpret the results of any trials that compared two interventions without use of a no intervention or placebo control with caution and planned to consider the results as important only if at least one of the interventions was shown to be effective by comparison with a no intervention or placebo control in other trials.
We did not include the following interventions:
- Treatment of HCV in re-infected liver graft. This intervention was studied in a different review (Gurusamy 2009).
- Treatment for HCV infection while waiting for liver transplant.
- Comparative trials of different immunosuppressive regimens. Different immunosuppressive regimens are associated with different risks of recurrence. However, an immunosuppressive regimen is a necessary concomitant therapy in patients undergoing liver transplantation. Identifying the regimen with less likelihood of facilitating recurrence is not the same clinical question as administering a specific antiviral treatment to prevent recurrence.
Types of outcome measures
- Patient mortality.
- 90-day mortality.
- Mortality at maximal follow-up.
- Graft survival.
- 90-day retransplantation.
- Graft survival at maximal follow-up.
- Quality of life.
- Adverse events.
- Serious adverse events were defined as any event that would increase mortality, was 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).
- Haematological adverse events such as anaemia, leukopenia, thrombocytopenia.
- Liver decompensation (long-term).
- Graft rejection requiring treatment.
- Requiring retransplantation.
- Requiring full course of medical treatment.
- Others requiring no treatment or where the information on treatment was not available.
- Fibrosis worsening (however defined by authors).
- Intensive therapy unit stay (for interventions that started during liver transplantation).
- Hospital stay (for interventions that started during liver transplantation).
- Recurrence of hepatitis C infection (hazard ratio (HR) of recurrence (however defined by authors).
We planned to present patient mortality, graft survival, and quality of life data in a Summary of findings table.
Search methods for identification of studies
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and WHO ICTRP (World Health Organization International Clinical Trials Registry Platform portal (apps.who.int/trialsearch/)) to February 2013. The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and ISRCTN among other registers. We have given the search strategies 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 or CT identified the trials for inclusion independently of each other. KG and ET or CT listed the excluded trials with the reasons for the exclusion. We resolved any differences in opinion through discussion.
Data extraction and management
KSG and ET or CT independently extracted the following data.
- Year and language of publication.
- Inclusion and exclusion criteria.
- Adult or paediatric.
- Orthotopic or heterotopic liver transplantation.
- Population characteristics such as age, gender of donor; and age, gender and MELD score of recipients.
- Warm ischaemic time.
- Number undergoing retransplantation.
- Immunosuppressive therapy.
- Other co-existing viral diseases.
- Viral subtype.
- Outcomes (mentioned above).
- Risk of bias assessment (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 trial reports shared the same patients, completely or partially (by identifying common authors and centres), we contacted the authors of the trials to clarify whether the trial had been duplicated. We resolved differences in opinion through discussion.
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and the Cochrane Hepato-Biliary Group Module (Gluud 2013). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a), we assessed the risk of bias of the trials based on the following bias risk domains.
- 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).
- 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 have been 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 were 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 was 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 high risk of bias in all domains as those of low risk of bias.
Measures of treatment effect
For binary outcomes, we calculated the risk ratio (RR) with 95% confidence interval (CI). RR calculations do not include trials in which no events occurred in either group, whereas risk difference calculations do. We planned to report the risk difference if the conclusions using this association measure were different from RR. For continuous outcomes, we calculated the mean difference (MD) with 95% CI for outcomes such as hospital stay and the standardised mean difference (SMD) with 95% CI for quality of life (where different scales might be used). For time-to-event outcomes such as long-term survival or recurrence, we calculated the HR with 95% CI.
Unit of analysis issues
The unit of analysis were individual patients undergoing liver transplantation or who had undergone liver transplantation with no evidence of recurrence of hepatitis C viral infection.
Dealing with missing data
We sought any unclear or missing information by contacting the authors of the individual trials. We performed an intention-to-treat analysis whenever possible (Newell 1992). We planned to impute data for binary outcomes using various scenarios such as best-best scenario, worst-worst scenario, best-worst scenario, and worst-best scenario (Gurusamy 2009; Gluud 2013).
For continuous outcomes, we used available-case analysis. We imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and used the median for the meta-analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the CIs, we imputed the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation will decrease the weight of the study for calculation of MDs and bias the effect estimate to no effect in case of SMD (Higgins 2011).
For time-to-event outcomes, we calculated the natural logarithm of the HR and its standard error using methods suggested by Parmar et al (Parmar 1998).
Assessment of heterogeneity
We explored heterogeneity using the Chi
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.
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.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses:
- Trials with low risk of bias compared with trials with high risk of bias.
- Adult compared with paediatric liver transplantation.
- Primary transplantation compared with retransplantation.
- HCV genotype I compared with other genotypes.
- With and without steroid in the immunosuppressive regimen.
- With and without azathioprine in the immunosuppressive regimen.
- With and without OKT3 in the immunosuppressive regimen.
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 last name of the first author. We planned to construct the trial sequential monitoring boundaries on the basis of the required diversity-adjusted information size (Wetterslev 2008; Wetterslev 2009).
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 were necessary on this topic (if the trial sequential 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). For Intensive therapy unit stay and hospital stay, the required sample size was calculated from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta-analysis results of low risk of bias trials and a minimal clinically relevant difference of one day. Trial sequential analysis cannot be performed for SMDs and so we did not plan to perform trial sequential analysis for these outcomes.
We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best-best scenario, worst-worst scenario, best-worst scenario, and worst-best scenario in the presence of missing outcome data (Gurusamy 2009; Gluud 2013). We also planned to perform a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.
Description of studies
We identified 2411 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (255 references), MEDLINE (536 references), EMBASE (820 references), and Science Citation Index Expanded (800 references). We excluded 631 duplicates and 1745 clearly irrelevant references through reading abstracts. We retrieved 35 references for further assessment. We identified one reference through scanning reference lists of the identified randomised trials (Mazzaferro 2003). We excluded 15 references for the reasons listed in the Characteristics of excluded studies table. Twelve randomised trials described in 21 references fulfilled the inclusion criteria. Of the 12 trials, 10 trials provided data for the review. The reference flow is shown in Figure 1. Details about the sample size, patient characteristics, the 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.
|Figure 1. Study flow diagram.|
A total of 501 liver transplant recipients undergoing liver transplantation for chronic HCV infection were randomised in 12 trials to various interventions and controls (Sheiner 1998; Singh 1998; Belli 2001; Reddy 2002; Willems 2002; Mazzaferro 2003; Chalasani 2005; Davis 2005; Shergill 2005; Schiano 2006; Charlton 2007; Chung 2013). Ten trials including 441 liver transplant recipients provided data for this review (Sheiner 1998; Singh 1998; Belli 2001; Reddy 2002; Mazzaferro 2003; Chalasani 2005; Davis 2005; Schiano 2006; Charlton 2007; Chung 2013). All the trials included patients who had undergone or were undergoing liver transplantation for HCV infection. There was no fibrosis in the patients at the time of inclusion (inference from the timing of the interventions or by histological testing). Three trials excluded patients undergoing liver retransplantation (Sheiner 1998; Davis 2005; Schiano 2006). One trial included one patient undergoing liver retransplantation (Singh 1998). It was not clear whether the remaining trials included retransplantation. In two other trials, it is clear that these trials did not include patients undergoing liver retransplantation because of the information provided in the baseline characteristics table (Chalasani 2005; Shergill 2005). The mean or median age of the participants ranged between 46 and 59 years in the trials that reported this variable (Singh 1998; Reddy 2002; Mazzaferro 2003; Chalasani 2005; Davis 2005; Schiano 2006; Charlton 2007; Chung 2013). The proportion of females in the different trials ranged from 0% to 41% (Singh 1998; Reddy 2002; Mazzaferro 2003; Chalasani 2005; Davis 2005; Schiano 2006; Charlton 2007; Chung 2013). The proportion of patients who had HCV infection genotype I ranged from 49.4% to 100% (Sheiner 1998; Singh 1998; Chalasani 2005; Davis 2005; Schiano 2006; Charlton 2007; Chung 2013).
The various comparisons in the trials are shown below. We selected 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.
The comparisons include the following.
- Interferon plus ribavirin versus no intervention (Reddy 2002): 32 patients were randomised to interferon plus ribavirin (n = 21) and no intervention (n = 11).
- Pegylated interferon versus no intervention (Chalasani 2005): 54 patients randomised to pegylated interferon (n = 26) or no intervention (n = 28).
- Pegylated interferon plus ribavirin versus no intervention (Charlton 2007): 115 patients randomised to pegylated interferon plus ribavirin (n = 55) or no intervention (n = 60).
- Ribavirin versus no intervention (Belli 2001): 19 patients randomised to ribavirin (n = 11) or no intervention (n = 8).
- Ribavirin plus interferon versus interferon (Shergill 2005): 44 patients were randomised to ribavirin plus interferon (n = 22) or interferon (n = 22). This trial did not provide any data for this review.
- Ribavirin plus interferon versus interferon versus no intervention (Mazzaferro 2003): 63 patients were randomised to ribavirin plus interferon (n = 22), interferon (n = 21), or no intervention (n = 20). This was included for the comparisons interferon versus no intervention; ribavirin plus interferon versus no intervention; and ribavirin plus interferon versus interferon.
- HCV antibody (high dose) versus HCV antibody (low dose) versus placebo or no intervention (Willems 2002; Davis 2005; Schiano 2006): 58 patients were randomised to HCV antibody (high dose) (n = 20), HCV antibody (low dose) (n = 20), or inactive control (n = 18). Placebo was used in two trials (Willems 2002; Schiano 2006), and no intervention was used in the other one (Davis 2005), as controls. Two trials were included for the comparisons HCV antibody versus inactive control and HCV antibody (high dose) versus HCV antibody (low dose) (Davis 2005; Schiano 2006). Willems 2002, which included 16 patients, did not report any of the outcomes of interest for this review. HCV antibody (MBL-HCV1) versus placebo (Chung 2013): 13 patients randomised to antibody (n = 6) or placebo (n = 5). There were two post-randomisation drop-outs in this trial. This trial was included for the comparison HCV antibody versus control.
Risk of bias in included studies
The risk of bias in the different trials is shown in Figure 2 and Figure 3. None of the trials had adequate generation of allocation sequence or allocation concealment. Three trials had adequate blinding by the use of placebo (Willems 2002; Schiano 2006; Chung 2013). Four trials were free from bias due to incomplete outcome data (Willems 2002; Mazzaferro 2003; Davis 2005; Schiano 2006). A published protocol was not available for any of the trials. Three trials reported all mortality and retransplantation and hence we considered them to be free from selective outcome reporting (Sheiner 1998; Singh 1998; Davis 2005). None of the trials were free from the vested interest bias. We considered all the trials to be of high risk of bias.
|Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.|
|Figure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.|
Effects of interventions
See: Summary of findings for the main comparison Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (mortality); Summary of findings 2 Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation (retransplantation)
The results were analysed using Review Manager 5 (RevMan 2012), although there were data only from one or two trials under each comparison used to obtain the RR and MD with the 95% CI. None of the trials reported the proportion of patients who developed liver decompensation, primary graft non-function, or quality of life (all comparisons); or Intensive therapy unit stay or hospital stay (for interventions that started during liver transplantation).
There was no significant difference in the proportion of patients who died within 90 days or at maximal follow-up for any of the comparisons that reported these outcomes ( Analysis 1.1; Analysis 1.2). There was no significant difference in the HR of death for comparisons that reported the HR of death ( Analysis 1.3).
Trial sequential analysis could be performed for 90-day mortality for the HCV antibody versus placebo and HCV antibody (high dose) versus HCV antibody (low dose) comparisons; and the mortality at maximal follow-up for the interferon versus control comparison. The proportion of patients recruited was less than 3% of the diversity-adjusted required information size (DARIS) and so trial sequential boundaries were not drawn. The conventional boundaries were not crossed (Figure 4; Figure 5; Figure 6).
There was no significant difference in the proportion of patients who required retransplantation at 90 days or at maximal follow-up for any of the comparisons that reported these outcomes ( Analysis 1.4; Analysis 1.5). HR of retransplantation was not reported in any of the trials. One trial reported that there was no significant difference in graft survival but did not provide the exact data (Charlton 2007).
Trial sequential analysis could be performed for retransplantation at maximal follow-up for the interferon versus control comparison. The proportion of patients recruited was less than 1% of the DARIS and so trial sequential boundaries were not drawn. The conventional boundaries were not crossed (Figure 7).
There was no significant difference in the proportion of patients with serious adverse events between the groups in any of the comparisons except for the comparison between pegylated interferon plus ribavirin versus no intervention(RR 1.79; 95% CI 1.03 to 3.12) ( Analysis 1.6). There was no significant difference in the proportion of patients who developed anaemia between the groups in any of the comparisons except for the comparison between pegylated interferon plus ribavirin versus no intervention (RR 11.07; 95% CI 1.51 to 81.47) ( Analysis 1.7). There was no significant difference in the proportion of patients who developed leukopenia between the groups in any of the comparisons ( Analysis 1.8). Trial sequential analysis was not performed since there were no comparisons with more than one trial.
There was no significant difference in the proportion of patients who developed graft rejections requiring retransplantation, graft rejections requiring steroids or equivalent drugs, or other graft rejections between any of the comparisons ( Analysis 1.9; Analysis 1.10; Analysis 1.11). One trial reported that there was no significant difference in biopsy-confirmed acute graft rejection rates but did not provide the exact data (Charlton 2007).
Trial sequential analysis could be performed for graft rejection requiring steroids or equivalent drugs for the comparison 'interferon versus no intervention'. Neither the trial sequential boundaries nor the conventional boundaries were crossed by the cumulative Z curve (Figure 8).
There was no difference in the proportion of patients with worsening of fibrosis in the comparisons in which this was reported ( Analysis 1.12). Trial sequential analysis was not performed since there were no comparisons with more than one trial.
Recurrence of hepatitis C infection
There was no significant difference in the virological titre at maximal follow-up or HR for recurrence of HCV infection in the comparison that reported this outcome ( Analysis 1.13). Trial sequential analysis was not performed for HR.
Variations in statistical analysis
There was no significant change in results by adopting the random-effects model in the few outcomes where more than one trial was included.
We did not perform a subgroup analysis because of the few trials included under each comparison.
We did not perform a funnel plot because of the few trials included under each comparison.
Summary of main results
This review evaluates a number of various antiviral interventions for prevention of recurrence of viral hepatitis C infection in patients who had undergone liver transplantation for HCV-induced chronic infection. There was no significant difference in patient mortality, graft rejection, or retransplantation in any comparison in the few trials that reported these outcomes. Quality of life and liver decompensation were not reported in any of the trials. These are the main clinical outcomes that should determine whether antiviral therapy should be used for the treatment of recurrent liver graft infection with HCV. However, the patients were followed up only for 24 to 26 weeks after the end of treatment (ie, a total of around 17 to 18 months) as virological outcomes were the principal outcomes in these trials. 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 required reduction in dose or cessation of therapy. Up to 90.9% of patients required reduction in dose, and up to 35.7% of patients required cessation of treatment in the various comparisons either because of adverse effects or because of patient's choice to stop treatment (Gurusamy 2010). There was no statistically significant difference in the serious complications such as graft rejection or retransplantation. The trials were underpowered to assess acute cellular rejection and the period of follow-up was too short to assess chronic rejections. The use of interferon, which can stimulate immunity, has the potential to increase the incidence of rejection. This suggests the necessity of close monitoring of these patients and in any future randomised trial.
Considering the lack of clinical benefit and the frequent adverse effects, there is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation.
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 prophylactic antiviral treatment to prevent recurrence of HCV infection is performed. Most of the issues have been discussed in the Cochrane review titled the 'Antiviral therapy for recurrent liver graft infection with HCV' by this group (Gurusamy 2009). However, these issues are discussed again as there are some variations in the trial design and also to enable the reader to obtain the information from this review rather than from another review.
One of the important issues that should be considered before a trial assessing the role of antiviral therapy for recurrent liver graft infection with HCV is initiated, is the groups to which the patients will be randomised. Considering that there is no evidence for benefit of any of the interventions, at least one of the groups in the trials should be 'no treatment' or 'placebo'. One of the other issues in the design of the trial is the safety of the treatment. As mentioned previously, adverse effects such as thrombocytopenia, leukopenia, or anaemia may require reduction in dose or cessation of therapy. Evidence from one randomised clinical trial showed that granulocyte colony-stimulating-factor is effective in normalising neutropenia induced by interferon and ribavirin therapy in patients with chronic viral hepatitis (Sharvadze 2007). Evidence from three randomised clinical trials showed that epoetin alfa (recombinant erythropoietin) is effective in 83% to 100% of patients (with chronic HCV 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 of the antiviral interventions. For this reason, it may be necessary to allocate some patients to a group in which the use of these growth factors is allowed.
The use of sustained virological response as a surrogate outcome in patients undergoing liver transplantation has not been validated (Gluud 2007; Brok 2010). Cirrhosis develops in only about 6% of patients at five years after liver transplantation (Yilmaz 2007). Even if the antiviral treatment reduces the cirrhosis by 50%, a large sample size is necessary to identify such a difference. About 80% of patients undergoing liver transplantation for chronic HCV infection survive for five years or more (Forman 2002). Any difference in survival is likely to be noted only after five years. Thus, the main outcomes that need to be assessed are patient survival, graft survival, quality of life, and liver decompensation (to determine if the treatment improves the quality-adjusted life years and to perform economic evaluation). Thus, the trial should be adequately powered, should use the appropriate methodology and outcomes, and should include a long period of follow-up to determine the important outcomes.
The other important issue is the timing of intervention. Theoretically, the risk of reinfection of the liver graft with HCV virus begins when the new liver is implanted. Most of the trials included patients within four weeks of liver transplantation. However, some of the trials included patients within 26 weeks of liver transplantation (Charlton 2007). Inclusion of such patients might result in significantly different findings compared with trials in which the patients received the treatment during or after liver transplantation. Patients who have not had any recurrence in six months might be at a lower risk of reinfection because of 'natural selection'.
Trialists are likely to face several problems. One of the issues is the genotype and initial viral load, which may influence the outcomes. Randomisation with stratification for these factors may be necessary. Stratification may also have to be performed on the basis of whether the transplantation is primary transplantation or retransplantation. The second issue is the choice of the experimental drug. 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 during the trial. Protocols should be in place for such an eventuality. The third issue is that of blinding the patients. Since the duration of treatment is 48 to 52 weeks and weekly injections are required for interferon (pegylated or non-pegylated), the blinding of the patients will be difficult, unpractical, and possibly unethical. This will result in bias in the quality of life measures. However, the main outcomes such as patient survival, graft survival, or liver decompensation are less unlikely to be affected by lack of patient blinding (Savovic 2012; Savovic 2012a). 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 patients lost to follow-up.
Another important issue is sample size calculations. In one study based on 11,036 liver transplant recipients in the United Network for Organ Sharing (UNOS) Scientific Registry for Liver (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 HCV infection as compared with 76.6% in non-HCV patients (Forman 2002). The actuarial five-year graft survival rate was 56.8% in liver transplants performed for HCV infection versus 67.7% in non-HCV patients. In another retrospective study (Ghobrial 1999), the five-year retransplantation rate was 76/374 (20.3%) after a median follow-up of 22.7 months. The retransplantation rate directly related to HCV 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 it may not be a suitable objective outcome measure. If survival is chosen as the primary outcome, the presence of hepatocellular carcinoma along with HCV infection may be a confounding factor (if a significant proportion of the patients have hepatocellular carcinoma). This may necessitate two different trials or one trial with a planned subgroup analysis of patients with and without hepatocellular carcinoma. This is because of the significantly lower survival in patients undergoing liver transplantation for malignancy (Forman 2002). The proportion of patients 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.
The longer period of follow-up in the trials will also allow the evaluation of whether sustained virological response is a valid surrogate marker of patient survival after liver transplantation for HCV infection (Gluud 2007; Gurusamy 2013). A valid surrogate marker will allow further trials to use a shorter period of follow-up. However, until such validation, it is misleading to designate a treatment an effective treatment just because it increased the proportion of patients who achieved sustained virological response without any clinical benefit.
Consent for organ donation by the organ donors was not reported in any of the trials. Future trials should report this information.
Overall completeness and applicability of evidence
Most of the trials in this review included patients undergoing primary liver transplantation. There is no evidence to suggest that patients undergoing retransplantation for recurrent HCV infection will respond differently from those undergoing primary liver transplantation for HCV infection.
Quality of the evidence
The quality of the evidence was very low, as shown in Summary of findings for the main comparison and Summary of findings 2. However, it must be noted that this is the best quality of evidence that is available currently.
Potential biases in the review process
We followed the Cochrane Handbook for Systematic Reviews of Interventions for this review (Higgins 2011). We did not blind the trials when extracting data or assessing the risk of bias and low risk of play of chance, but assessments were done independently and in duplicate. We applied no language, publication status, or sample size restrictions. Thus, we minimised the bias due to selection of trials. In spite of an extensive search of literature, there is a possibility of publication bias. Because of the few trials included in this review with few participants and outcomes, there is a high risk of random errors.
Agreements and disagreements with other studies or reviews
There is no change in the conclusions from the previous version of this review (Gurusamy 2010).
Implications for practice
There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation.
Implications for research
Further randomised clinical trials are necessary to evaluate whether patients undergoing liver transplantation for HCV infection need prophylactic antiviral treatment. Such trials must also include a control group (untreated group) to determine if treatment provides any benefit.
To The Cochrane Hepato-Biliary Group for the support that they have provided.
First published version
Peer reviewers: Ronald Koretz, US; Tullia Maria de Feo, Italy.
Contact editor: Christian Gluud, Denmark.
Second published version
Peer reviewers: Graem JM Alexander, UK; Panagis Lykoudis, UK.
Contact editor: Norberto C Chavez-Tapia, Mexico.
This project was funded by the National Institute for Health Research.
Disclaimer of the Department of Health: "The views and opinions expressed in the review are those of the authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), National Health Services (NHS), or the Department of Health".
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Search strategies
Last assessed as up-to-date: 14 February 2013.
Contributions of authors
KS Gurusamy wrote the review, assessed the trials for inclusion, and extracted data on included trials.
E Tsochatzis and C Toon independently identified trials and extracted the data on included trials.
AK Burroughs and BR Davidson critically commented on the review and provided advice for improving the review.
Declarations of interest
Sources of support
- none, Not specified.
- Hellenic Association for the Study of the Liver, Greece.Dr E Tsochatzis receives an educational grant for his research in UK
- National Institute for Health Research, UK.This research was funded by NIHR Cochrane grant
Differences between protocol and review
We have divided the outcomes into primary and secondary outcomes and ordered them by clinical importance. We have defined the retransplantation and graft rejection outcomes clearer, that is, as those occurring after the start of therapy. We have added liver decompensation to the primary outcomes, as this is an important clinical outcome that can be influenced by treatment. We have revised the methods of assessing the risk of bias in the different trials according to the updated version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We have clearly stated the methods for obtaining information on hazard ratio.
Differences between first and second version
We have revised and reordered the outcomes by importance to the patient and healthcare provider. We have revised the methods of assessing the risk of bias in the different trials according to the updated version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Medical Subject Headings (MeSH)
*Liver Transplantation; Antiviral Agents [adverse effects; *therapeutic use]; Genotype; Graft Rejection [epidemiology]; Graft Survival; Hepacivirus [*genetics]; Hepatitis C, Chronic [*drug therapy; mortality; prevention & control; *surgery]; Interferon-alpha [adverse effects; therapeutic use]; Polyethylene Glycols [adverse effects; therapeutic use]; Recombinant Proteins; Ribavirin [adverse effects; therapeutic use]; Secondary Prevention
MeSH check words
* Indicates the major publication for the study