Antiviral therapy for recurrent liver graft infection with hepatitis C virus
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the benefits and harms of different anti‐viral therapies in patients with hepatitis C re‐infected grafts after liver transplantation.
Background
In the United Kingdom, the annual incidence of liver transplantation is 14 per one million population (NHS UK Transplant). In the USA, the annual incidence of liver transplantation is 21 per one million population (OPTN/SRTR 2005). 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). 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 transplant can be performed in adults or in children (Lim 2006). Worldwide, there is a demand for liver transplants in surplus of supply. Recently 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 cirrhosis is one of the main causes for liver transplantation (Eason 2001). Nearly half of the patients who undergo liver transplantation for hepatitis C virus cirrhosis have recurrence of hepatitis C virus in the graft (Jain 2002). Immunosuppressive regimens, which avoid steroids, are reported to have a lower rate of graft infection with hepatitis C virus than those which 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 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).
Anti‐viral agents like 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). Sustained virological response by quantitative PCR (polymerase chain reaction) was achieved in 12% of patients (Chalasani 2005) and the viral load was significantly lower than the 'no treatment' group (Chalasani 2005). In another trial, HCV became undetectable by qualitative PCR in 17% to 61% of patients who had hepatitis re‐infection of the graft (Gane 1998; 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).
We have not been able to identify any systematic reviews or meta‐analyses assessing the role of the antiviral therapy in patients with hepatitis C re‐infected grafts after liver transplantation.
Objectives
To compare the benefits and harms of different anti‐viral therapies in patients with hepatitis C re‐infected grafts after liver transplantation.
Methods
Criteria for considering studies for this review
Types of studies
We will consider all randomised clinical trials, which assess anti‐viral 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). Quasi‐randomised trials (where the method of allocating participants to a intervention are not strictly random, for example, date of birth, hospital record number, alternation) will be excluded.
Types of participants
Patients with hepatitis C viral re‐infection of the liver grafts (however defined by authors) irrespective of age, cadaveric or living donor, indication for liver transplantation, first or re‐transplantation, the immunosuppressive therapy used.
Types of interventions
We will include any antiviral treatment in patients with hepatitis C re‐infected liver grafts versus no intervention, placebo, or another antiviral treatment.
We will not include the following interventions:
(1) Prophylactic treatment of hepatitis C virus in patients who do not have re‐infection of the liver graft, as this will be considered in a different review (Gurusamy 2007).
(2) Treatment for hepatitis C virus infection while waiting for liver transplant.
Types of outcome measures
(1) Mortality (30‐days mortality and mortality at maximal follow‐up).
(2) Decrease in viral load of hepatitis C virus (however defined by authors).
(3) Histological changes in the liver due to hepatitis C virus infection (however defined by authors).
(4) Adverse events defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment, but resulting in a dose reduction or discontinuation of treatment (ICH‐GCP 1997). Severe adverse events were defined as any event that would increase mortality; is life‐threatening; requires inpatient hospitalisation; results in a persistent or significant disability; or any important medical event, which may jeopardise the patient or require intervention to prevent it.
(5) Rejection of liver transplant requiring treatment.
(6) Re‐transplantation.
(7) Initial poor function.
(8) Primary graft non function.
(9) Intensive therapy unit stay.
(10) Total hospital stay.
Search methods for identification of studies
We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). We have given the preliminary search strategies in Table 01 with the time span for the searches. As the review progresses, we will improve the search strategies if necessary.
We will also search the references of the identified trials to identify further relevant trials.
Data collection and analysis
Trial selection and extraction of data
KSG and KS, independently of each other, will identify the trials for inclusion. The excluded studies with the reasons for the exclusion will be listed.
KSG and KS will independently extract 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) Orthotopic or heterotopic liver transplantation.
(7) Population characteristics such as age, gender of donor; and age, gender and MELD score of recipients.
(8) Number undergoing re‐transplantation.
(9) Immunosuppressive therapy.
(10) Other co‐existing viral diseases.
(11) Co‐interventions.
(12) Viral sub‐type.
(13) Baseline viral load.
(14) Baseline histological changes.
(15) Outcomes (mentioned above).
(16) Methods of identifying hepatitis C virus infection and measuring viral load.
(17) Methodological quality (described below).
(18) Sample size calculation.
(19) Intention‐to‐treat analysis.
We will seek any unclear or missing information clarified by contacting the authors of the individual trials. If there is any doubt whether the trials share the same patients ‐ completely or partially (by identifying common authors and centres) ‐ we will contact the authors of the trials to clarify whether the trial has been duplicated.
We will resolve any differences in opinion through discussion and in case of unsettled disagreements, BRD will adjudicate.
Assessment of methodological quality
KSG and KS will assess the methodological quality of the trials independently, without masking of the trial names. The authors will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006) and The Cochrane Hepato‐Biliary Group Module (Gluud 2006). Due to the risk of biased overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001), we will look at the influence of methodological quality of the trials on the results by evaluating the reported randomisation and follow‐up procedures in each trial. If information is not available in the published trial, we will contact the authors in order to assess the trials correctly. We will assess generation of allocation sequence, allocation concealment, blinding, and follow‐up.
Generation of the allocation sequence
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Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
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Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
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Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and will be excluded from the review.
Allocation concealment
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Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, or sealed envelopes.
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Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
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Inadequate, if the allocation sequence was known to the investigators who assigned participants. Such studies will be excluded.
Blinding
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Adequate, if the trial was described as double blind.
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Unclear, if the trial was described as double blind, but the method of blinding was not described.
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Not performed, if the trial was not double blind.
Double blinding will not be assessed since we expect that there will be no 'double‐blind' trials. However, we will record whether any of the outcomes were assessed by a blinded observer or blinded assessor.
Follow‐up
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Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
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Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
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Inadequate, if the number or reasons for dropouts and withdrawals were not described.
Statistical methods
We will perform the meta‐analyses according to the recommendations of The Cochrane Collaboration (Higgins 2006) and the Cochrane Hepato‐Biliary Group Module (Gluud 2006). We will use the software package RevMan 4.2 (RevMan 2003). For dichotomous variables, we will calculate the relative risk (RR) with 95% confidence interval. For continuous variables, we will calculate the weighted mean difference (WMD) with 95% confidence interval. We will use a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987). In case of discrepancy between the two models we will report both results; otherwise we will report only the results from the fixed‐effect model determined by the quantity of heterogeneity. Heterogeneity will be explored by chi‐squared test with significance set at P value 0.10, and the quantity of heterogeneity will be measured by I2 (Higgins 2002). If the results in the fixed‐effect and random‐effects model do not differ, we will report the fixed‐effect model. Otherwise, we will report both model results.
We will adopt the 'available‐case analysis' (Higgins 2006). The analysis will be performed on an intention‐to‐treat basis (Newell 1992). In case we find 'zero‐event' trials in statistically significant outcomes, we will perform a sensitivity analysis with and without empirical continuity correction factors as suggested by Sweeting et al (Sweeting 2004). We will also report the risk difference.
Subgroup analysis
We will perform the following subgroup analyses:
‐ trials with adequate methodology compared to trials with unclear or inadequate methodologies.
‐ adult compared to paediatric liver transplantation.
‐ HCV genotype Ib compared to other genotypes.
Funnel plot
We will use a funnel plot to explore bias (Egger 1997; Macaskill 2001). Asymmetry in funnel plot of trial size against intervention effect will be used to assess this bias. We will perform linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997).
