Antiviral medication for preventing cytomegalovirus disease in solid organ transplant recipients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to assess the benefits and harms of antiviral medications for preventing symptomatic CMV disease in solid organ transplant recipients of all ages, irrespective of CMV sero‐status prior to transplantation. The secondary aims are to evaluate the efficacy of antiviral medications in preventing all CMV infection (symptomatic and asymptomatic where CMV is detected only by laboratory investigation) and in decreasing the incidence of acute rejection, graft loss, death (all cause mortality and mortality due to CMV disease), opportunistic infections and to evaluate the harms of each antiviral medication.
Firstly, the review will compare studies of antiviral medications with placebo/no treatment. Secondly, it will explore comparisons between two or more antiviral agents and/or two different doses of the same antiviral agent. Thirdly, it will compare the treatment effect of each regimen between different solid organs and finally, between the different risk groups (i.e. pre‐existent CMV sero‐status and/or level of immunosuppression).
Background
Cytomegalovirus (CMV) is the most common virus pathogen in solid organ transplant recipients being a major cause of morbidity and mortality during the first six months post‐transplant (Fishman 1998; Rubin 2000). The overall incidence of symptomatic CMV disease in the transplant population ranges from 30 to 50% with the incidence and severity being highest among lung recipients (Linden 2000). Approximately 50% of deaths following lung transplantation are attributed to infection (Michaels 2000). Like all herpes viruses, CMV has the propensity to establish lifelong 'latency' infection in the host after the initial infection has resolved. Therefore, a solid organ recipient may be infected either by exogenous virus or by reactivation of latent virus if they were CMV positive pre‐transplant. Those at highest risk of symptomatic CMV disease are CMV sero‐negative patients who receive organs from CMV sero‐positive donors, and CMV sero‐positive patients on heavily immunosuppressive regimens (Fishman 1998; Rubin 2000).
CMV may manifest as a non‐specific illness characterised by fever, mononucleosis, leucopenia and thrombocytopenia, or as a variety of clinical syndromes including pneumonitis, hepatitis, encephalitis and focal gastrointestinal disease. In addition, CMV causes morbidity in organ recipients through indirect effects on their immune response (Rubin 1989), and is associated with increased risk of allograft injury and rejection (Grattan 1989; Keenan 1991), opportunistic infections (Fishman 1995; Hadley 1995; Van den Berg 1996) and late onset malignancies such as EBV‐lymphoproliferative disease (Basgoz 1995). For these reasons, many strategies have been proposed to prevent CMV infection, and /or prevent systematic disease. Two main strategies to prevent CMV disease have been adopted: prophylaxis of all organ recipients with antiviral agents and/or immunoglobulins, or 'pre‐emptive therapy' or 'targeted therapy' for high‐risk groups (Rubin 1989). The latter usually relies upon monitoring for CMV infection by newly available sensitive techniques such as antigenemia or polymerase chain reaction (PCR) that allow the diagnosis to be made much earlier than traditional culture methods (Emery 2000).
There remains a lack of consensus on the merits of the various CMV prophylaxis protocols available (Fishman 1998). A meta‐analysis of prophylactic treatment versus placebo/no treatment is currently published in the Cochrane Library (Couchoud 1998). As it is now due for an update, more recent articles comparing prophylaxis with antiviral medications (including acyclovir, ganciclovir, valacyclovir, valganciclovir) will be included. In addition this review has been modified to include studies comparing one prophylactic antiviral medication with another. In this review we will examine the effect of prophylaxis with antiviral agents in recipients of solid organ transplant recipients on CMV disease, all CMV infection, the incidence of acute rejection, graft loss, opportunistic infections and death. We will compare the treatment effect of each regimen between different solid organs and between different risk groups. Finally, the study will evaluate potential harms caused by antiviral medications, namely nephrotoxicity, bone marrow suppression, and emergence of resistant CMV strains. Subsequent reviews will evaluate pre‐emptive therapy on detection of CMV viraemia and the use of other agents (immunoglobulins, vaccines) alone or in combination with antiviral medications.
Objectives
The aim of this review is to assess the benefits and harms of antiviral medications for preventing symptomatic CMV disease in solid organ transplant recipients of all ages, irrespective of CMV sero‐status prior to transplantation. The secondary aims are to evaluate the efficacy of antiviral medications in preventing all CMV infection (symptomatic and asymptomatic where CMV is detected only by laboratory investigation) and in decreasing the incidence of acute rejection, graft loss, death (all cause mortality and mortality due to CMV disease), opportunistic infections and to evaluate the harms of each antiviral medication.
Firstly, the review will compare studies of antiviral medications with placebo/no treatment. Secondly, it will explore comparisons between two or more antiviral agents and/or two different doses of the same antiviral agent. Thirdly, it will compare the treatment effect of each regimen between different solid organs and finally, between the different risk groups (i.e. pre‐existent CMV sero‐status and/or level of immunosuppression).
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials and quasi‐randomised controlled trials will be included.
Types of participants
Participants of all ages, irrespective of CMV sero‐status prior to transplantation, who have undergone at least one solid organ transplant (kidney, liver, lung, heart, pancreas). Bone marrow and other cellular transplants will be excluded.
Types of interventions
Interventions will include antiviral medications (including acyclovir, ganciclovir, valacyclovir, valganciclovir). Comparisons will be made between antiviral medications and placebo/no treatment, two different antiviral medications, or two varying doses of an antiviral medication.
Trials of pre‐emptive treatment (i.e. treatment on detection of CMV viraemia), immunoglobulin alone or with antiviral medications, vaccines or interferon will be excluded. Treatment regimens for symptomatic CMV disease will be excluded.
Types of outcome measures
The primary outcome measures will be the incidence of symptomatic CMV disease and all cause mortality. Secondary outcomes include the incidence all CMV infection (symptomatic and asymptomatic), acute rejection, graft loss, death, opportunistic infections, time to CMV disease, harms (including nephrotoxicity, bone marrow suppression, and emergence of resistant CMV strains). All outcomes will be recorded as present/absent.
CMV infection will be as defined by the investigators. This is usually the isolation of CMV from a cultured specimen from any site, or positive histopathology or CMV antigen detection in a tissue specimen, or the presence of CMV p65 antigenemia, or an elevation in CMV viral load as detected by quantitative PCR (as defined by the investigator). 'Symptomatic CMV disease' will be as defined by the investigator. This is usually the diagnosis of CMV infection in association with one or more of the following: CMV syndrome (temperature of 38oC or more with no other documented source in association with one or more atypical lymphocytosis, leukopenia or thrombocytopenia), pneumonitis, focal gastrointestinal disease, liver function abnormality, or encephalitis. Asymptomatic infection will be defined by the diagnosis of CMV infection in the absence of symptoms, only when there had been systematic monitoring for CMV infection during the study. Graft loss will be defined as the need for dialysis for renal transplantation or re‐transplantation for other organs during the follow‐up period of the study. Acute rejection will be defined as used by the individual authors. This is either biopsy proven or clinical, defined by rise in creatinine levels with respect to kidney transplants or response to rejection treatment.
Search methods for identification of studies
A systematic and comprehensive literature search will be carried out to identify eligible RCTs. The Cochrane Central Register of Controlled Trials (CENTRAL ‐ in The Cochrane Library) will be searched using the following search terms as Medical Subject Heading (MeSH) and text words:
cytomegalovirus
cytomegalovirus‐infection
CMV
transplantation (including organ‐transplantation, kidney‐transplantation, heart‐transplantation, lung‐transplantation, liver‐transplantation, and pancreas‐transplantation)
acyclovir
ganciclovir
valacyclovir
valganciclovir
cidofovir
immunoglobulin
vaccine and immunotherapy
The Cochrane Renal Group's Specialised Register will also be searched in a similar manner. Two reviewers will (DV, CJ) independently search MEDLINE (1966‐to most recent) and EMBASE (1980‐to most recent) without language restriction. An optimally sensitive search strategy developed for identification of RCTs (Dickerson 1995; Lefebvre 1996) will be combined with MeSH and text words, as outlined below.
MEDLINE search strategy:
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 randomized controlled trials/
4 random allocation/
5 double blind method/
6 single blind method/
7 or/1‐6
8 animal/ not (animal/ and human/)
9 7 not 8
10 clinical trial.pt.
11 exp clinical trials/
12 (clin$ adj25 trial$).ti,ab.
13 cross‐over studies/
14 (crossover or cross‐over or cross over).tw.
15 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
16 placebos/
17 placebo$.ti,ab.
18 random$.ti,ab.
19 research design/
20 or/10‐19
21 20 not 8
22 21 or 9
23 exp cytomegalovirus/ or exp cytomegalovirus infection/
24 exp organ transplantation/
25 24 not exp bone transplantation/
26 23 and 25
27 exp acyclovir/ or exp ganciclovir/ or exp antiviral agents/
28 ac?clovir.tw./ or ganc?clovir.tw./ or valac?clovir.tw./ or valganc?clovir.tw./ or cidofovir.tw.
29 exp immunoglobulins/ or exp gamma‐globulins/ or exp immunoglobulins, intravenous/ or exp immunotherapy/
30 27 or 28 or 29
31 26 and 30
32 22 and 31
EMBASE search strategy:
1 exp clinical trial/
2 evidence based medicine/
3 outcomes research/
4 crossover procedure/
5 double blind procedure/
6 single blind procedure/
7 prospective study/
8 major clinical study/
9 exp comparative study/
10 placebo/
11 "evaluation and follow up"/
12 follow up
13 randomization/
14 or/1‐13
15 controlled study/ not case control study
16 or/14‐15
17 (clinic$ adj5 trial$).ti,ab.
18 ((single$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
19 (control$ or prospectiv$ or volunteer$).ti,ab.
20 random$.ti,ab.
21 placebo$.ti,ab.
22 or/17‐21
23 16 or 22
24 limit 23 to human
25 exp cytomegalovirus/ or exp cytomegalovirus infection
26 exp kidney transplantation/ or exp heart transplantation/ or exp lung transplantation/ or exp liver transplantation/ or exp pancreas transplantation
27 25 and 26
28 exp aciclovir/ or exp ganciclovir/ or exp valaciclovir/ or valganciclovir/ or exp antiviral agents/ or exp immunoglobulin/ or exp immunotherapy
29 ac?clovir.tw./ or ganc?clovir.tw./ or valac?clovir.tw./ or valganc?clovir.tw./ or cidofovir.tw.
30 28 or 29
31 27 and 30
32 24 and 31
The Trials Search Coordinator will be contacted to ensure all relevant trials have been identified. Additional studies will also be located through article reference lists and through contact with local and international experts in the field.
Data collection and analysis
Included and excluded studies
Two reviewers (EH, CJ,) will independently screen titles and abstracts retrieved from the searches and identify those trials that meet the inclusion criteria. This process will favour over‐selection in order to include all relevant trials. The full article will be retrieved if uncertainty exists or when the abstract is not available. Any disagreement with article selection will be resolved through discussion and consultation with a third reviewer (JC).
Two of four reviewers (EH, CJ, PB, KK) will independently extract data from eligible studies. Participant characteristics (number, age, sex, comorbidities), intervention (type of treatment, dose, duration, co‐interventions) and primary and secondary outcome measures will be recorded. Authors will be contacted to obtain relevant raw data, as well as any missing information. Any discrepancies in data extraction will also be discussed with a third reviewer (JC) and resolved. In the instance where results of a study are published more than once, the most complete data will be extracted from all sources and used in the analysis only once.
Study quality
The quality of studies to be included was assessed independently by two of four reviewers (EH, CJ, PB, KK) without blinding to authorship or journal of publication using the checklist developed for the Cochrane Renal Group. Discrepancies were resolved by consensus and when necessary by discussion with JC. The quality items assessed were allocation concealment, intention‐to‐treat analysis, completeness of follow‐up and blinding of investigators, participants and outcome assessors (Hollis 1999; Juni 1999; Moher 1998; Schultz 1995).
Quality checklist
1. Allocation Concealment
Adequate: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
Unclear: Randomisation stated but no information on method used is available
Inadequate: Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
2. Blinding
Blinding of investigators: Yes/No/not stated
Blinding of participants: Yes/No/not stated
Blinding of outcome assessor: Yes/No/not stated
Blinding of data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group could be identified in >20% of participants due to side effects of treatment or the treatment groups could be identified through different routes or frequency of administration of trial medications.
3. Intention‐to‐treat analysis
Yes: specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment
No: not reported and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomised but were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation).
Not stated: not reported and could be determined (Studies with 100% follow up of patients included so that patient exclusion after randomisation cannot be excluded)
4. Completeness of follow‐up:
Percentage of participants lost to follow up or with no data for the primary outcome of effectiveness
Statistical assessment
Dichotomous outcomes will be expressed as relative risks with 95% confidence intervals while continuous outcomes are stated as weighted mean differences. Data will be pooled using a random effects model to calculate a summary estimate of effect. Heterogeneity will be formally tested using Cochran's Q statistic and the I2 statistic (Higgins 2003). To determine whether there is any difference between study results due to plausible effect modifiers, subgroup analysis will be performed, given sufficient number of studies for analysis. The analysis will explore the effects of patient characteristics such as type of solid organ transplanted, type of intervention, dose and duration of intervention, level of pre‐existent risk, timing and methods used for diagnosis of CMV infection, time to graft loss, HHV6/7 status, and quality of study on treatment effect.
