Prevention of CMV in Liver Transplant Recipients
February 1, 1998 3 minutes read
Prevention of CMV in Liver Transplant Recipients
ABSTRACT & COMMENTARY
Synopsis: Orally administered ganciclovir was superior to placebo in the prevention of CMV disease in liver transplant recipients.
Source: Gane E, et al. Randomized trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. Lancet 1997;350: 1729-1733.
Gane and colleagues at 15 centers in the united States and Europe evaluated the safety and efficacy of orally administered ganciclovir in the prevention of CMV disease in 304 adult primary liver transplant recipients. Recipients of multiple organs and CMV seronegative recipients of livers from CMV seronegative donors were excluded, as were those unable to take oral medication or who had neutropenia (< 1000/uL), thrombocytopenia (< 25,000/uL), or increased creatinine (> 300 umol/L). Patients were randomized to receive either 1000 mg ganciclovir or matching placebo tid beginning within 10 days of transplantation and continuing through day 98.
Kaplan-Meier estimates of the incidence of CMV disease (symptomatic illness with positive WBC CMV antigen, positive CMV culture, or seroconversion) at six months were 18.9% in the placebo recipients and 4.8% in those assigned ganciclovir (< 0.001), representing a 78% reduction. Thirteen (8.5%) placebo recipients developed "tissue-invasive" disease, while only one (0.7%) ganciclovir recipient did so (P = 0.001). Ganciclovir was beneficial in all subgroups studied, including seronegative recipients of seropositive livers, those who received anti-lymphocyte antibody preparations, recipients of cyclosporin or tacrolimus, and those who underwent rejection.
The incidence of herpes simplex infections was also reduced by oral ganciclovir administration from 23.5% to 3.5% (relative risk, 0.13 [95% CI 0.05-0.32]; P < 0.001). There was no significant difference between the treatment groups in the incidence of acute or chronic graft rejection or of graft loss or death. No deaths were directly attributable to CMV disease. There was no significant difference in adverse events. Patients who developed CMV disease while receiving prophylaxis responded to treatment with intravenously administered ganciclovir.
COMMENT BY STAN DERESINSKI, MD, FACP
CMV infection continues to represent a significant risk for solid organ allograft recipients, particularly, but not exclusively, for CMV seronegative recipients of organs from seropositive donors. Up to 100% of recipients falling into the latter group undergo primary CMV infection, and one-half to three-quarters of these develop CMV disease. Being a seronegative recipient from a seropositive donor is a strong independent predictor of mortality at one year post-transplantation. One-year mortality in this group has been reported to be 44% vs. 11% in seronegative recipients from seropositive donors (Falagas ME, et al. Ann Intern Med 1997;126:275-279).
As a consequence, much attention is being given to developing methodologies to prevent CMV infection and disease. An alternative approach to prophylaxis of CMV disease is pre-emptive therapy, with drug administered only to those with some marker of CMV activity, such as a positive blood culture or antigenemia, but prior to the development of CMV disease. Evidence to date, however, indicates that this strategy is less effective than a prophylactic strategy.
A recent study of prophylaxis of CMV infection in liver transplant recipients found that a regimen consisting of 14 days of intravenously administered ganciclovir followed by oral acyclovir was superior to oral acyclovir alone (Badley AD, et al. Transplantation 1997;64:66-73). However, the incidence of infection remained high even in the combined modality group, with 11% overall developing CMV disease.
Prolonged intravenous administration of ganciclovir was markedly superior to "high dose" (800 mg qid) oral acyclovir in preventing CMV disease in liver transplant recipients. The incidence of CMV disease was only one (0.8%) of 124 ganciclovir recipients (Winston DJ, et al. Lancet 1995;346:69-74). Although possibly misleading, it is of interest to compare this with the 4.8% incidence in the oral ganciclovir recipients in the study reviewed here.
Orally administered ganciclovir has limited bioavailability, which could account for possibly lesser prophylactic efficacy than intravenously administered ganciclovir. One approach that seems rational may be to use oral ganciclovir prophylaxis in relatively low-risk individuals and to use the intravenous form in high-risk solid organ recipients. In the meantime, work continues on better predictors of benefit from pre-emptive therapy as well as on new antiviral agents.
Which of the following is correct?
a. Liver transplant recipients who are CMV seronegative and who receive organs from CMV seropositive donors are at lowest risk of developing CMV disease.
b. Orally administered ganciclovir has very high bioavailability.
c. The administration of oral ganciclovir to liver transplant recipients was associated with an decreased risk of herpes simplex infection.
d. Liver transplant recipients who develop CMV disease while receiving oral ganciclovir must be treated with a regimen other than intravenously administered ganciclovir.
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