Antiviral drugs used as protective and preventive therapy reduce CMV disease and CMV-associated deaths in solid organ transplant recipients

Cytomegalovirus (CMV; a herpes virus) is the most common type of virus detected in people who have received solid organ transplants (kidney, heart, liver, lung and pancreas). CMV disease is a major cause of illness and death during the first six to 12 months after transplantation. Two main strategies to prevent CMV disease have been adopted: protection and prevention (prophylaxis) of viral infections for all organ recipients using antiviral drugs, or 'pre-emptive therapy' of organ recipients, who develop evidence of CMV infection during routine screening.

We looked at the benefits and harms of antiviral prophylaxis to prevent CMV disease in people who are solid organ transplant recipients. The evidence we found shows that some antiviral drugs (ganciclovir, valaciclovir and aciclovir) reduced the risk of CMV disease, death due to CMV disease, clinical disease caused by herpes simplex and herpes zoster viruses, bacterial infections and protozoal infections.

For CMV disease and death, the relative benefits of aciclovir, ganciclovir and valaciclovir appear consistent across recipients of heart, kidney and liver transplants. These benefits occur in both CMV positive transplant recipients and CMV negative transplant recipients of CMV positive donor organs, with or without the inclusion of antilymphocyte antibody therapy, and the benefits were seen at all measured time points. We found that ganciclovir is more effective than aciclovir and as effective as valganciclovir, which is currently the most commonly used antiviral drug to prevent CMV disease in transplant recipients.

Extended duration of prophylaxis was found to be more effective than three months of therapy in kidney and lung transplant recipients. More studies are needed to determine the optimum duration and dosage of antiviral drugs for all solid organ transplant recipients.

Authors' conclusions: 

Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. These data suggest that antiviral prophylaxis should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants.

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Background: 

The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis with the aim of preventing the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008.

Objectives: 

To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause mortality in solid organ transplant recipients.

Search strategy: 

We searched MEDLINE, EMBASE and the Cochrane Central Registry of Controlled Trials (CENTRAL) in The Cochrane Library to February 2004 for the first version of this review. The Cochrane Renal Group's specialised register was searched to February 2007 and to July 2011 for the first and current updates of the review without language restriction.

Selection criteria: 

We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications and comparing different regimens of the same antiviral medications in recipients of any solid organ transplant. Studies examining pre-emptive therapy were excluded.

Data collection and analysis: 

Two authors independently assessed study eligibility, risk of bias and extracted data. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and by mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed using restricted maximum-likelihood to estimate the between study variance. Multivariate meta-regression was performed to investigate whether the results were altered after allowing for differences in drugs used, organ transplanted, and recipient CMV serostatus at the time of transplantation.

Main results: 

We identified 37 studies (4342 participants). Risk of bias attributes were poorly performed or reported with low risk of bias reported for sequence generation, allocation concealment, blinding and selective outcome reporting in 25% or fewer studies.

Prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment significantly reduced the risk for CMV disease (19 studies; RR 0.42, 95% CI 0.34 to 0.52), CMV infection (17 studies; RR 0.61, 95% CI 0.48 to 0.77), and all-cause mortality (17 studies; RR 0.63, 95% CI 0.43 to 0.92) primarily due to reduced mortality from CMV disease (7 studies; RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduced the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but not fungal infection, acute rejection or graft loss.

Meta-regression showed no significant difference in the relative benefit of treatment (risk of CMV disease or all-cause mortality) by organ transplanted or CMV serostatus; no conclusions were possible for CMV negative recipients of negative organs.

Neurological dysfunction was more common with ganciclovir and valaciclovir compared with placebo/no treatment. In direct comparison studies, ganciclovir was more effective than aciclovir in preventing CMV disease (7 studies; RR 0.37, 95% CI 0.23 to 0.60) and leucopenia was more common with aciclovir. Valganciclovir and IV ganciclovir were as effective as oral ganciclovir. The efficacy and adverse effects of valganciclovir/ganciclovir did not differ from valaciclovir in three small studies. Extended duration prophylaxis significantly reduced the risk of CMV disease compared with three months therapy (2 studies; RR 0.20, 95% CI 0.12 to 0.35). Leucopenia was more common with extended duration prophylaxis but severe treatment associated adverse effects did not differ between extended and three month durations of treatment.

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