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In utilizing a preemptive strategy to minimize the occurrence of symptomatic cytomegalovirus (CMV) infection following liver transplant, only patients with proven CMV activity by direct detection are treated. We applied the following preemptive strategy for CMV infection to 49 sequential liver transplant recipients between 1998 and 2001. Patients were monitored for CMV activity using CMV p65 antigen assay for the first 10 months of the study. Thereafter, we changed the detection method to a quantitative PCR for plasma CMV-DNA. All patients were monitored post transplant, weekly for the first 3 months and then monthly. Only patients with detected CMV activity were treated with ganciclovir. Patients were divided into four groups, based on donor (D) and recipient (R) CMV status. In seven out of 49 patients (14.3%) CMV activity was detected: four in group D +/R –, and three in group D –/R –. Five out of these seven patients had asymptomatic CMV infection. Symptomatic CMV infection developed only in two of these seven patients, to give total rate of 4.1% (2/49). All seven patients developed CMV IgG antibody. ‘Transient’ CMV replication detected by PCR in five patients in group D +/R+ was not defined as infection. No patients developed organ-invasive CMV disease. The cost of anti-CMV treatment using the preemptive strategy was $1000/patient/1st year. Using preemptive strategy, early detection of CMV infection was achieved, allowing timely treatment. The use of ganciclovir for CMV infection in only 4.3% of the patients should have a positive impact on minimizing the risk of ganciclovir-resistant virus, and should reduce the cost of CMV prevention strategies.
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Cytomegalovirus (CMV) remains a cause of morbidity and mortality in liver transplant recipients, despite the increasing use of ganciclovir. The highest incidence of CMV infection occurs in CMV-IgG negative recipients (R –) who received organs from CMV-IgG positive donors (D +). However, a 6–11% incidence of CMV infection has been reported in R – recipients of organs from CMV-IgG negative donors (1).
Numerous preventive strategies have been utilized to decrease the incidence of symptomatic CMV disease following liver transplantation (2–4). Using ‘universal prophylaxis’, ganciclovir is administered immediately after transplantation and continued for a prolonged period in all transplant recipients, irrespective of their risk group. The potential development of ganciclovir-resistant CMV has recently been mentioned as a downside of this strategy (5). The ‘targeted prophylaxis’, promotes administration of ganciclovir to patients who are at high risk for CMV infection at the time of transplantation, as in the D +/R – combination (6). The ‘preemptive strategy’ involves screening patients routinely for evidence of CMV activity (antigen, PCR) so that timely treatment with ganciclovir can be initiated at the detection of CMV activity (2,3). At that time-point the patient is usually symptom free. In the present study we have evaluated the efficacy of the ‘preemptive strategy’ in preventing symptomatic CMV infection and organ-invasive CMV disease in liver transplant recipients.
Materials and Methods
Our institutional review board approved this study of 51 patients who received 53 liver transplants between January 1998 and September 2001 at the University of Massachusetts Medical Center. Two patients who died within the first 30 days after transplant were excluded, leaving 49 patients as the study group. The median follow-up period was 15 months (3–33 months). Tacrolimus and steroids formed the basis of the standard immunosuppressive regimen. As prophylaxis for Herpes simplex and Herpes zoster, patients received oral acyclovir 800 mg four times daily for 1 year. Patients, to whom OKT3 was given for steroid-resistant rejection, received prophylactic intravenous (i.v.) ganciclovir during the period of OKT3 administration (10–14 days). We have defined CMV infection to include: (i) ‘Asymptomatic infection’: no clinical symptoms, CMV activity is detected by CMV pp65 antigen assay, PCR, or serologic host response (7–9); (ii) ‘Symptomatic CMV infection’: patients have clinical symptoms of mild to moderate severity and present with fever, anorexia, malaise and pancytopenia (frequently called ‘CMV disease’); and (iii) ‘Organ-invasive CMV disease’: less commonly patients develop a severe organ-invasive process (3).
A preemptive strategy for CMV infection was adopted and applied to all liver recipients irrespective of their risk-groups. Patients were prospectively monitored for CMV activity weekly for the first 3 months after transplantation and then monthly for about 6 months.
For the first nine patients who had transplants during the first 10 months of the study, CMV activity was monitored using a CMV pp65 antigen assay (qualitative result only). Thereafter, the method of detection available to us was a real-time quantitative whole-blood CMV DNA PCR (Specialty Laboratories in California, USA). This method was used on the other consecutive 40 patients.
CMV DNA was detected in whole-blood specimens using a modification of the TAQman (TM) PCR method licensed from Roche Molecular Systems. Initially, 250 μl of whole blood is processed to recover a DNA pellet. The CMV DNA is selectively amplified using 10 μl of purified DNA to 40 μl of TAQman Universal Master Mix (Perkin Elmer) with the addition of the CMV specific primers. The limit of detection for this assay is 5 copies/assay or 200 copies of CMV DNA/mL. Detection of CMV above this level is considered positive and below this level is considered negative.
Initiation of ganciclovir therapy was triggered by first detection of CMV activity. For CMV IgG positive recipients, we held the initiation of ganciclovir treatment in cases of a low level of detection by laboratory assay in an asymptomatic patient. In these patients treatment was initiated only following repeat positive detection. If symptoms developed without detected CMV activity, ganciclovir therapy was initiated only following a confirmatory CMV activity test. In all cases, ganciclovir therapy included intravenous ganciclovir at the standard induction dose (5 mg/kg every 12 h) adjusted for renal function, for 4–7 days, followed by oral ganciclovir treatment (1000 mg orally three times a day), for a total of 3 months. The cost of the ganciclovir treatments was monitored by our pharmacy.
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Of the 49 patients included in the study, 19 were in the D +/R + group, 12 in the D –/R + group, 6 in the D +/R – group, and 12 in the D –/R – group (Table 1). In the R + groups there were no cases of CMV infection. Five patients in the D +/R + group developed transient CMV activity (low PCR detection on one test and negative PCR repeat assay with no treatment).
Table 1. : CMV infection status by risk group
|CMV status D/R*||D +/R +||D –/R +||D +/R –||D –/R –|
|Asymptomatic CMV infection||none||none||3|| 2|
|Symptomatic CMV infection||none||none||1|| 1|
|Organ-invasive CMV disease||none||none||none||none|
|‘Transient’ CMV activity|| 5||none||none||none|
In the R – groups, seven patients developed CMV infection with a total rate of 14.3% (7/49 pt.), and a rate of 38.9% (7/18 pt.) in the R – groups. Table 2 outlines these seven patients with regard to the assay used, time of CMV infection, PCR values, and IgG status.
Table 2. : Patients with cytomegalovirus infection after transplantation
|CMV status> D/R*||Assay||CMV first||First value||Symptomatic||CMV IgG|
|used||detected||for PCR copies/mL||CMV infection||seroconversion|
|D pos/R neg||Antigen||4 weeks||Pos||no||yes|
|D pos/R neg||PCR||6 weeks||5600||no||yes|
|D pos/R neg||PCR||12 weeks||3160||yes||yes|
|D pos/R neg||PCR||29 weeks||3708||no||yes|
|D neg/R neg||PCR||6 weeks||30 339||yes||yes|
|D neg/R neg||PCR||2 weeks||4736||no||yes|
|D neg/R neg||PCR||Not detected||Not detected||no||yes|
Only two patients, 4.1% (2/49 pt.) developed symptomatic CMV infection evidenced by fever, malaise, and pancytopenia and detection of the virus by PCR assay. These two patients were in the R – group, one in the D +/R – and one in the D –/R –, with symptomatic CMV infection rate of 16.7% (1/6 pt.) and 8.3% (1/12 pt.), respectively. All seven patients with CMV infection developed CMV-IgG antibody. The overall rate of symptomatic CMV infection in the R – groups was 11.1% (2/18 pt.). In the 49 patients studied there was no case of organ-invasive CMV disease. Six patients received i.v. ganciclovir during OKT3 treatment of steroid-resistance rejection.
The cost to our pharmacy of acyclovir is $0.23/800 mg tablet ($332 for 12 months), ganciclovir is $3.49/250 mg tablet ($3780 for 3 months) and i.v. ganciclovir is $60 per day ($840 for 2 weeks) (Table 3). Based on this cost, the calculated cost of our anti-CMV therapy in the 49 patients was $1000/patient/1st year. This cost includes the cost of the acyclovir for all patients, and the cost of ganciclovir therapy for the seven patients with CMV infection and for the six patients who were treated with OKT3.
Table 3. : Cost of antiviral agents (wholesale)
|Oral acyclovir||$0.23/800 mg tablet||$322 for 12 months|
|Oral ganciclovir||$3.49/250 mg tablet||$3780 for 3 months|
|I.v. ganciclovir||$30.21/500 mg i.v. vial||$840 for 2 weeks|
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Despite the recent advances in antiviral therapy, CMV disease continues to be a significant concern after liver transplantation. Multiple therapeutic approaches have been devised with varying degrees of success. Frequent monitoring and early detection of CMV activity form the basis of the preemptive strategy, reserving initiation of antiviral chemotherapy for patients with evidence of CMV activity in most cases before symptoms develop. We have detected CMV activity requiring treatment by our protocol at a rate of 14.3%, with symptomatic CMV infection at a rate of 4.1%. The two patients with symptomatic CMV infection were in the R – groups, with a rate of 16.7% in the D +/R – group, and 8.3% in the D –/R – group. These rates are comparable to the rate of symptomatic CMV infection in the group that received oral ganciclovir in the multicenter study by Gane et al. (10). In our study the preemptive approach proved to be as effective as a prophylactic approach in controlling CMV infection, even in the patients at highest risk (D +/R –). Our rates of CMV infection may actually be a little higher because six patients were treated with ganciclovir as prophylaxis during a course of OKT3 therapy. Ganciclovir-resistant CMV has been reported in transplant patients on prophylactic ganciclovir (5). Therefore, limiting the use of ganciclovir exclusively for documented CMV infection (14.3% in our study) may have a positive impact on minimizing the risk of ganciclovir-resistant CMV. In fact, in our patients we did not encounter CMV resistant to ganciclovir. Although this study is based on a relatively small patient population, adoption of the preemptive approach by other transplant centers would result in significant reduction in the total use of ganciclovir. The use of the preemptive strategy in our patients resulted in a very acceptable rate of symptomatic CMV infection (4.1%), with no cases of organ-invasive CMV disease. These results should be attributed to the early detection and intervention, before patients developed high titers of CMV in the blood. The pharmaceutical cost of our preemptive strategy ($1000/patient/1st year) is very reasonable and compares favorably with other CMV control strategies (2,6,11). With the availability of oral valganciclovir ($23.43 for a 450-mg tablet), a drug that results in serum levels of ganciclovir comparable to the intravenous form, further studies similar to that of Paya et al. (12) with oral ganciclovir are needed to define its role and its cost in treating and preventing CMV infectionTable 3.
Although we administered the high-dose oral acyclovir for H. simplex and H. zoster prophylaxis, it may have had an anti-CMV effect. The efficacy of oral acyclovir in preventing CMV infection has been the source of debate in kidney transplant recipients or kidney-pancreas allograft recipients (3). Although, this group of patients appears to benefit from high-dose oral acyclovir or oral valacyclovir with respect to prevention of CMV infection (13), this beneficial effect has not been successfully reproduced in liver transplant recipients (14).
Low-level detectable CMV activity by PCR is one of the problems inherent in using this very sensitive assay. Low-level or transient CMV activity was detected in five patients, all in the D +/R + group. This may represent a false positive result due to lab technique, contamination, or it may reflect transient viremia that spontaneously cleared. Although we do not believe that these transient viremias represent CMV infection, recent studies question the clinical significance of such findings and argue that these low levels may have a deleterious effect on these patients (4,15). Although, a low level of CMV activity may not necessarily result in symptomatic CMV infection, it may influence other post-transplantation complications.