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Preemptive Use of Oral Ganciclovir to Prevent Cytomegalovirus Infection in Liver Transplant Patients: A Randomized, Placebo-Controlled Trial

  1. Carlos V. Paya1,2,4,
  2. Jennie A. Wilson4,
  3. Mark J. Espy2,
  4. Irene G. Sia1,
  5. Michael J. DeBernardi3,4,
  6. Thomas F. Smith2,
  7. Robin Patel1,2,4,
  8. Greg Jenkins5,
  9. William S. Harmsen5,
  10. David J. Vanness5 and
  11. Russell H. Wiesner4
  1. Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota
  2. Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota
  3. Department of Pharmacy, Mayo Clinic, Rochester, Minnesota
  4. Transplant Center, Mayo Clinic, Rochester, Minnesota
  5. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  1. Reprints or correspondence: Dr. Carlos V. Paya, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (paya{at}mayo.edu).
 
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Abstract

The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent infection and disease in solid-organ transplant patients has not been evaluated by placebo-controlled trials. We carried out such a study in 69 patients who had received liver transplants and had positive results of CMV polymerase chain reaction within 8 weeks after transplantation but did not have concomitant CMV infection or disease. These patients were randomly assigned to receive placebo or oral ganciclovir for 8 weeks. CMV infection developed in 21% and disease developed in 12% of placebo recipients (P = .022), compared with 3%and 0%, respectively, among ganciclovir recipients (P = .003). Similarly, in the placebo arm, 55% and 36% of CMV-negative patients who received organs from CMV-positive donors developed CMV infection or disease, respectively (P = .02), compared with 11% and 0% of such patients in the ganciclovir arm (P < .01). Oral ganciclovir administered on CMV detection by PCR prevents CMV infection or disease after liver transplantation.

A hallmark of cytomegalovirus (CMV) infection in transplant recipients is CMVdisease,which,when disseminated,may result in significant morbidity [1]. The available antiviral agents and newer diagnostic techniques have made it possible to reduce the incidence of CMV disease and the associated morbidity through implementation of more-effective preventive strategies [2]. Two such strategies are currently used for organ transplant patients: antiviral prophylaxis and preemptive therapy. Randomized, placebo- controlled studies have demonstrated the efficacy (albeit incomplete) of prophylaxis with ganciclovir or valacyclovir [3, 4]. In addition, these studies highlight the fact that many patients (specifically, CMV-positive recipients [R+] of liver transplants) are at low risk of developing CMV disease, even when they are treated with placebo, thus calling into question the need for prophylaxis for such patients. Unnecessary prophylaxis can be avoided by the use of preemptive therapy [5], in which diagnostic tests are used to detect CMV in peripheral blood and thus to identify patients carrying the pathogen so that treatment with antiviral agents can be administered before CMV disease develops. However, despite the widespread use of preemptive therapy, there is a paucity of randomized studies that clearly establish its effectiveness or highlight its limitations; those studies that have been carried out [6, 7] were not placebo controlled.

The optimal microbiological test and cutoff point that identify patients at risk for CMV disease also remain to be established [8]. Moreover, and on the basis of the natural history of CMV infection in the absence of prophylaxis, such tests detect CMV within 3–6 weeks after transplantation, a time when the patient is in an outpatient setting. Until now, this has led to the use of intravenous (iv) access placement and prolonged courses of antiviral drug treatment, which not only are cumbersome but require patient hospitalization in some countries. Use of oral anti-CMV agents may allow physicians to circumvent this important practical limitation. Oral ganciclovir, although it is less effective than its iv formulation in suppressing CMV replication because of its limited bioavailability [9], could, theoretically, be effective in suppressing incipient levels of replicating CMV detected by a sensitive diagnostic test before the patient develops CMV disease.

To establish the cost of preemptive therapy and its effectiveness in preventing CMV infection and disease in organ transplant patients, and to evaluate the use of oral ganciclovir in such a setting, we conducted a prospective, double-blind, randomized, placebo-controlled trial. Oral ganciclovir and polymerase chain reaction (PCR) were used in a preemptive therapeutic approach for patients who were not receiving antiviral prophylaxis. The inclusion of a placebo arm in the study made it possible to investigate the natural history of CMV infection in patients in whom a PCR-based test detected evidence of CMV replication.

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Subjects, Materials, and Methods

Study design and protocol description. During the first 8 weeks after liver transplantation, blood samples were obtained on a weekly basis from patients who consented to the study. Samples were processed in parallel to detect CMV DNA by PCR and CMV replication by use of the shell vial culture (SVC) technique [10]. Detection of CMV DNA by PCR in 1 blood sample, in the absence of a positive SVC, triggered random assignment to the group of patients receiving placebo or the group receiving ganciclovir (1 g orally 3 times a day, adjusted to renal function) for 8 additional weeks. During the second 8-week period, patients receiving placebo or ganciclovir were followed by weekly surveillance of CMV replication in blood by use of the SVC. Those patients who were not randomly assigned to receive ganciclovir or placebo during the first 8 weeks after transplantation (n = 16) were followed up by weekly surveillance with SVCs for an additional 8 weeks. The total time for intensive microbiological surveillance was 16 weeks (4 months, or 110 days). During the 16-week study period, each patient was routinely evaluated for any evidence of CMV disease. Although the results obtained in the present study were gathered during the strict 4-month follow-up period, an additional post hoc analysis was done at 1 year after transplantation. The surgical liver transplantation technique, immunosuppression, and non-antiviral antimicrobial prophylaxis regimens have been described elsewhere [11].

The primary end point of the study was development of CMV infection, which triggered the administration of iv ganciclovir. Secondary end points included development of CMV disease or other opportunistic infections, allograft rejection, and patient death. Administration of OKT3 for the treatment of steroid-refractory allograft rejection was considered to be an additional secondary end point, because such patients required concomitant treatment with iv ganciclovir, in accordance with the current clinical practice guidelines of our Mayo Clinic liver program.

“CMV infection” was defined as the detection of CMV replication by SVC or by histologic evidence and/or evidence on immunostaining of CMV in body tissues. The definition of “CMV disease” required documentation of CMV infection, as described above, and appropriate clinical manifestations [12].

Patients receiving oral or iv ganciclovir, foscarnet, or CMV hyperimmune immunoglobulin were excluded from the study. Acyclovir was administered orally (200 mg 3 times a day) to all patients during the first 21 days after transplantation to prevent herpes simplex virus infection. This dosage is not known to prevent CMV infection or disease [13].

The study drugs (ganciclovir and placebo) were supplied by Roche Diagnostics. Oral ganciclovir was formulated as blue, size-1, hard gelatin capsules, each containing 250 mg of ganciclovir and supplied in containers of 108 capsules each. Matching placebo capsules were also provided.

The unblinded study pharmacist maintained drug accountability records and stored all study drugs in a secure, locked location with appropriate pharmaceutical precautions, in accordance with the drug labeling. The pharmacist also randomly assigned eligible patients to ganciclovir or placebo, according to a predetermined randomization chart. Patients were instructed to return all unused study drugs and empty drug containers.

Patient population and exclusion criteria. One hundred sixtyeight consecutive adult (>18 years of age) patients undergoing a first liver transplantation who met study criteria were enrolled in the prospective weekly PCR and SVC assay surveillance protocol. Patients who were CMV negative (R−) and received organs from CMV-negative donors (and who therefore received CMV-negative blood products), were undergoing retransplantation or transplantation with an organ other than the liver, had CMV infection or disease at the time of transplantation, or were allergic to ganciclovir were excluded from the study. A second set of exclusion criteria was established for patients who enrolled in the surveillance study at the time of randomization. These criteria included inability to receive drugs orally, creatinine clearance level <20 mL/h, white blood cell count <1000 leukocytes/mm3, platelet count <25,000 platelets/mm3, or concomitant development of the study end points (CMV infection, CMV disease, or receipt of OKT3 and, therefore, iv ganciclovir).

Microbiological tests. The SVC assay used in the present study has been described elsewhere [10]. The CMV serostatus of patients was determined by microparticle EIA for IgG class antibody, using the AxSYM instrument (Abbott Laboratories).

Blood specimens used to detect CMV DNA were processed as follows: 5 mL of whole blood was collected into Vacutainer tubes containing EDTA (Sigma). Mononuclear cells and granulocytes were separated by Histopaque 1119 (Sigma) and mixed, yielding a population of peripheral blood leukocytes (PBLs). These were washed twice with PBS and resuspended in 2 mL of serum-free medium. DNA from PBLs was extracted by use of the IsoQuick extraction method (Qiagen), according to the manufacturer's instructions. The PCR has been described elsewhere [14]. Amplified PCR products were detected by use of the PCR ELISA kit (Roche), according to the manufacturer's instructions.

Statistical methods. Discrete factors, including sex, CMV donor/recipient serologic status, and use of immunosuppressive drugs before study randomization, were assessed by use of the χ2 test or Fisher's exact test, as appropriate. Continuous factors, such as age at transplantation and days between transplantation and first positive PCR test result were assessed by use of the Wilcoxon rank sum test. Development of opportunistic infections and allograft rejection that occurred in the time between transplantation and possible drug effectiveness were compared between groups, using timedependent covariates in a Cox survival model [15] and censoring at drug randomization, and analyzed with a log-rank test [16]. Patient survival free of CMV infection or disease and free of CMV disease only was assessed using the Kaplan-Meier method [17]. Significance testing for the effectiveness of oral ganciclovir was done by use of the Cox proportional hazards models in 2 ways: (1) Data from patients were analyzed, using the time since transplantation as the timeline for the baseline hazard. Patients were considered to be at risk for a study end point from the time of randomization forward [18]. (2) Time from transplantation to randomization was included as a covariate in the model. The timeline for survival began with randomization and followed forward. The association between PCR positivity and subsequent CMV disease or infection was assessed, using the Cox survival method, for patients who were not assigned to receive oral ganciclovir. Patients were followed up from the date of transplantation, with PCR positivity treated as a time-dependent covariate [15]. Data from patients who received subsequent iv ganciclovir were censored at the time of treatment.

Sensitivity, specificity, positive and negative predictive value, and accuracy were calculated for the prediction of CMV infection subsequent to a positive PCR test. Patients who received ganciclovir subsequent to a rejection episode were not included in this part of the analysis.

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Results

One hundred sixty-eight consecutive liver transplant patients were enrolled in the surveillance study (figure 1). CMV DNA was detected in 86 (51%) of these patients in PBLs during the first 8 weeks after transplantation. Of those 86 patients, 69 (80%) were randomly assigned to receive placebo or oral ganciclovir in a blinded fashion (table 1). The principle reason for exclusion of the remaining 17 patients (20%) for whom CMV DNA was detected in PBLs was concomitant CMV infection or disease at the time of randomization and initiation of study drug (13 [15%] of 86). This was more frequently observed among R− patients who received organs from CMV-positive donors (D+) (6 [23%] of 26) than among R+ patients (7 [12%] of 60) (table 1). No specific risk factors were identified for patients who were not assigned to receive placebo or ganciclovir because of concomitant CMV infection or disease.

Figure 1
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Figure 1

Study scheme. CMV, cytomegalovirus; PCR+, positive result of polymerase chain reaction; PCR−, negative result of polymerase chain reaction.

Figure 2
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Figure 2

Cytomegalovirus (CMV) infection and polymerase chain reaction (PCR) positivity. CI, confidence interval; D+, CMV-positive donor; R+, CMV-positive recipient; R−, CMV-negative recipient.

Table 1
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Table 1

Random assignment of cytomegalovirus (CVM)-positive liver transplant patients to receive ganciclovir or placebo, stratified by CMV serostatus.

The baseline characteristics of the 69 patients at the time of randomization are shown in table 2. There was an even distribution between both treatment groups with regard to most parameters, except that a larger proportion of patients in the placebo arm had acute allograft rejection. However, adjustment for rejection episodes before randomization in the analysis of oral ganciclovir efficacy demonstrated that this difference did not result in an increase in CMV end points.

Table 2
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Table 2

Characteristics of liver transplant patients who tested positive for cytomegalovirus (CMV) by polymerase chain reaction (PCR) at the time of random assignment to receive ganciclovir or placebo.

The efficacy of oral ganciclovir was determined by analysis of the cumulative probability of developing CMV infection after enrollment in the study. Both primary and secondary end points were analyzed in the overall patient population and in the CMV D+/R− subgroup. Ganciclovir administration on detection of CMV DNA in PBLs was effective in reducing the incidence of both CMV infection and disease and, consequently, the frequency of iv ganciclovir administration (table 3). This was observed in the overall study population and in the CMV D+/R− group. Acute allograft rejection, opportunistic infections, retransplantation, and patient death were infrequent, which precluded determination of the impact of preemptive treatment with oral ganciclovir.

Table 3
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Table 3

Occurrence of posttransplantation infections or complications in cytomegalovirus (CMV)-positive liver transplant patients receiving placebo or ganciclovir.

The study design also provided an opportunity to investigate the natural history of CMV infection and disease in relation to the results obtained by CMV DNA PCR. For this purpose, we excluded from the analysis the subgroup of patients in whomCMV DNA was detected by PCR and who were randomly assigned to receive oral ganciclovir. CMV infection or CMV disease alone developed in 41% of patients in whom CMV DNA was detected during the first 8 weeks after transplantation (table 4). These percentages were higher in the CMV D+/R− population (12 [71%] of 17). Four episodes of CMV infection developed during the first 16 weeks in 4 of the individuals in whom CMV DNA was not detected during the first 8 weeks after transplantation (4 [5%] of 82). Three of those 4 episodes were defined as CMV disease, and 2 of the episodes occurred in CMV D+/R− patients (table 4). From these data, it was also concluded that, in general, 59% of patients who have detectable CMV DNA in PBLs will not subsequently develop CMV infection, even if they are not treated with oral ganciclovir. However, this percentage is lower (29%) when the CMV D+/R− patient group is assessed.

Table 4
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Table 4

Relationship between polymerase chain reaction (PCR) test results and cytomegalovirus (CMV) infection or disease, stratified by CMV serostatus.

The time at which positive CMVPCR results were seen during the first 8 weeks after transplantation is shown in figure 2. In addition, figure 2 shows the probability of development of a positive PCR result on the basis of CMV donor and recipient serostatus, which was the only risk factor identified among 6 factors studied (age, sex, major histocompatibility class I or II mismatch, and allograft rejection were the other 5 factors). The specificity, sensitivity, and positive and negative predictive values of the PCR test with regard to the development of CMV infection and CMV disease alone are shown in table 5.

Table 5
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Table 5

Sensitivity, specificity, and predictive value of the polymerase chain reaction test in predicting cytomegalovirus infection in liver transplant patients.

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Discussion

This randomized, placebo-controlled study addressing the clinical usefulness of a PCR test in guiding preemptive treatment with an oral antiviral agent of patients who have undergone organ transplantation has yielded a number of novel and clinically relevant observations. Oral ganciclovir is effective in reducingCMV infection and CMV disease and thus, when it is administered at first detection (by use of a qualitative PCR-based technique) of CMV DNA in PBLs, reduces the use of iv ganciclovir. This applies not only to lower-risk (R+) but also to high-risk (D+/R−) patients.

This study also highlights the fact that, in 23% of CMV D+/R− patients, the PCR test yielded positive results in very close temporal relationship to the occurrence of CMV infection or disease, thus precluding the use of oral ganciclovir to prevent CMV infection and disease. Close analysis of those cases did not reveal any specific risk factor that could help to identify this subgroup of patients. This is similar to the results of another study, in which bone marrow transplant patients were treated preemptively with iv ganciclovir when culture-based testing was used [5] but not when PCR was used [19].

Multiple reasons may explain the relative failure of the qualitative PCR test in CMV D+/R− patients. First, the interval between blood collection and randomization may have been as long as 6 days because of sample and drug shipment and the turnaround time of the PCR test. Development of a rapid and automated PCR test could circumvent one of those limitations. It could also be argued that more-frequent sampling, such as twice weekly, from high-risk patients could have prevented some cases of CMV infection. Most likely, the rate and slope of viral replication may be so rapid that the time available for intervention with oral ganciclovir on the first detection of any evidence of replication, as detected by the qualitative PCR test, may be too short for treatment to be effective [20, 21]. It is our opinion that, for D+/R− patients, a preemptive therapeutic approach involving administration of oral ganciclovir in response to the results of a PCR-based test is too cumbersome, because most patients ultimately develop CMV infection and disease; thus, we consider it more practical to administer antiviral prophylaxis immediately after transplantation for these patients.

A recent non-placebo-controlled study in which antigenemia was the trigger for preemptive therapy also concluded that oral ganciclovir was effective [22]. Interestingly, the antigenemia test was nearly flawless in accurately identifying patients at risk. This is surprising, because PCRtests like the one used here,which detects as few as 20 copies of CMVDNA, have been recognized in multiple comparative studies to be more sensitive in detection of viral replication than is antigenemia [8]. Nevertheless, such discrepancies should alert the transplant community to the need for validation of a variety of nonstandardized tests or “homebrew assays” at each institution, if such testing is to become the standard of care for guiding preemptive therapy. Commercial molecular assays may overcome such limitations. It should be noted that all patients in the present study who required administration of anti-T cell receptor antibodies also received iv ganciclovir as part of our clinical practice. Elimination of this key risk factor [23, 24] may explain why patients in the R+ group did not develop CMV infection or disease in the absence of prophylaxis (as was highlighted by results of the placebo arm). This suggests that preexisting CMV immunity in the absence of OKT3 treatment is sufficient to suppress CMV replication, even in the setting of immunosuppression. Moreover, it is in this sub-group of patients (the largest in our study population) that the PCR test conveyed results opposite to those in the CMV D+/R− group. Hence,in the D+/R− group the positive predictive value was better, and in the R+ group, the negative predictive value was increased. Overall, this PCR test had a low predictive value; the results were transient in most patients, and therefore the test did not accurately identify patients who were at risk of subsequently developing CMV infection or disease. Had we required 2 consecutive positive PCR test results over the course of a 1- or 2-week period or used a specific cutoff point with a quantitative PCR test (had it been available), we could, theoretically, have increased the positive predictive value and specificity of the test. Regardless, and because the incidence of CMV infection and disease in this non-R+ group (when patients treated with OKT3 and iv ganciclovir are excluded) was very low, we question the need for intensive microbiological surveillance by PCR testing. Other alternatives, such as observation or short-term (e.g., 1 month) prophylaxis, could be considered.

In the few episodes of CMV infection and CMV disease that developed in the PCR-positive, oral ganciclovir-treated patients, clinical and virologic response to administration of iv ganciclovir was seen. Although this includes few cases, the approach described in this study does not appear to lead to the emergence of clinically relevant ganciclovir-resistant CMVstrains. Nevertheless, this possibility needs to be considered when an antiviral agent with poor bioavailability is used to treat patients with incipient CMV replication.

Finally, a post hoc data analysis through 1 year after transplantation revealed that 2 additional patients were treated for CMV infection or disease after the 16-week follow-up period. At 16.5 weeks after transplantation, a D+/R− patient randomly assigned to receive placebo was treated for CMV viremia and hepatitis, and, at 32 weeks after transplantation, an R− patient randomly assigned to receive and treated with ganciclovir for 8 weeks was treated for symptomatic CMV viremia.

In summary, this study demonstrates that oral ganciclovir can be used effectively to implement preemptive therapy, and it highlights the advantages and limitations of routine use of a PCR test in a placebo-controlled study. The recent approval of valganciclovir in the United States may benefit the implementation of this study, because the pharmacokinetic features of oral ganciclovir are improved in this prodrug [25]. We expect that these results will be helpful to the transplant community in guiding future clinical trials that will evaluate more-powerful oral antiviral agents and diagnostic testing to further investigate the usefulness of preemptive treatment as a valid strategy in preventing CMV disease in patients who have undergone organtransplantation.

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Acknowledgements

We are grateful to the liver transplant patients who agreed to participate in the present study and to our medical and paramedical colleagues in the Mayo Clinic Liver Transplant Unit.

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Footnotes

  • Informed consent was obtained from patients or their guardians. The human experimentation guidelines of the US Department of Health and Human Services and the Mayo Foundation Institutional Review Board were followed in conducting this study.

  • Financial support: Roche Pharmaceuticals (research grant).

  • Received August 14, 2001.
  • Revision received November 26, 2001.
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  1. J Infect Dis. (2002) 185 (7): 854-860. doi: 10.1086/339449
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