Original Article
A Controlled Trial of Ganciclovir to Prevent Cytomegalovirus Disease after Heart Transplantation
N Engl J Med 1992; 326:1182-1186April 30, 1992
- Abstract
- Abstract
Background.
Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation.
Methods.
This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28.
Results.
Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P<0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovirtreated patients had serum creatinine concentrations ≥220 μmol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient.
Conclusions.
The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness. (N Engl J Med 1992;326:1182–6.)
Article Activity
- Article
MANY heart-transplant recipients become infected with cytomegalovirus (CMV) with substantial short-term complications,1 including both systemic and focal CMV illness in the first months after transplantation as well as increased susceptibility to other opportunistic infections during the first year.2 CMV gastrointestinal disease and pneumonia are the most important short-term sequelae of CMV infection in heart-transplant recipients.1 CMV infections have also been associated with a higher incidence of coronary artery disease in the years after transplantation.3
Ganciclovir treatment produces improvement in the manifestations of disease due to CMV in this and other populations.4 In addition, ganciclovir was recently found to be useful in the treatment of CMV infection before manifestations appear. In a randomized, controlled trial,5 treatment with ganciclovir reduced the incidence of CMV pneumonia in asymptomatic recipients of bone marrow transplantation who had CMV-positive bronchoalveolar-lavage cultures. CMV shedding is also regularly suppressed by ganciclovir treatment4 — a good preliminary indicator of the drug's in vivo antiviral effects.
Ganciclovir is tolerated well in organ-transplant recipients who have CMV disease.6 It therefore seemed reasonable to evaluate early prophylactic use of this drug in a placebo-controlled, double-blind study in recipients of heart transplants.7 Our study evaluated the benefit of a prophylactic 28-day course of intravenous ganciclovir starting one day after transplantation. Because there was no previous experience with CMV prevention in this population of patients, a design was chosen that would affect events early in viral replication before the development of overt disease. In addition, the study regimen was appealing because it caused minimal interference with the normal postoperative activities of the patients.
Methods
Patients
Transplant recipients who were CMV-seropositive before transplantation or who received an organ from a CMV-seropositive donor were studied at Stanford University Medical Center, the University of Utah Medical Center, Latter-Day Saints Hospital, and the Salt Lake City Veterans Affairs Medical Center, the last three of which constituted the Utah Transplantation Affiliated Hospitals Cardiac Transplant Program. Because of the possibility of differences in incidence rates or mechanisms of infection, patients were stratified into two groups at randomization according to their CMV serologic status. Similar regimens of iatrogenic immunosuppression (including OKT3 antibody, corticosteroids, azathioprine, and cyclosporine) were used in both transplant programs for graft maintenance. Patients were excluded from the study if they had undergone combined heart—lung transplantation, had received any other antiviral drugs within the seven days before enrollment, or had leukocyte counts below 1.5×109 per liter (1500 per cubic millimeter), platelet counts below 50×109 per liter (50,000 per cubic millimeter), a creatinine clearance less than 10 ml per minute per 1.73 m2 of body surface, or a serum creatinine concentration above 400 μmol per liter (4.5 mg per deciliter). The committees for the use of human subjects at all the institutions approved the study design and the consent forms. The patients were stratified according to CMV serologic status and randomly assigned to receive ganciclovir or placebo in the transplant programs (Stanford and Utah). Each program's diagnostic virologic laboratory performed monthly isolations of CMV from urine and from biopsy or lavage specimens, immunofluorescence assays for CMV in biopsy specimens, and CMV serologic tests. Identical criteria were used by both programs to diagnose CMV disease.
Several types of CMV illness were prospectively defined in the protocol. CMV pneumonia was diagnosed when dyspnea, interstitial infiltrates, or hypoxemia was present and CMV was confirmed as present in lung tissue by bronchoalveolar lavage or lung biopsy. Such confirmation required a positive culture from the involved site, a finding of inclusions characteristic of CMV, or a positive immunochemical stain for CMV antigens. In most biopsy specimens all three confirmatory procedures were performed. CMV disease of the gastrointestinal tract was diagnosed by endoscopy that confirmed the presence of CMV in biopsy tissue. CMV syndrome was defined by a positive culture plus at least two of the following: a decrease in the white-cell count or the platelet count to less than 50 percent of the base-line value, hepatitis manifested by abnormal results of liver-function tests, or clinically important fever that was otherwise unexplained.
Drug Schedule
The study drug was administered only during the first month of the postoperative period, when patients are usually hospitalized or living near the transplant center. The study design did not require prolonged intravenous dosing, although it was recognized that a longer period of dosing might have protected patients throughout the time when they were at risk for disease. The study medication was usually begun on the day after heart transplantation, but in some patients its administration was delayed for as many as six days because of problems with acute care. Patients were given intravenous infusions of ganciclovir or placebo at a dosage of 5 mg per kilogram of body weight every 12 hours for 14 days, followed by 6 mg per kilogram once a day, 5 days per week for 2 weeks. Therapy was delayed (starting on days 2 to 7) in 22 percent of the patients, and this delay was distributed similarly in both groups (21 percent of the patients assigned to ganciclovir and 23 percent of those assigned to placebo). The dose was modified according to the patient's creatinine clearance, if this value was abnormal. This modification occurred in 38 percent of all patients (43 percent of the ganciclovir group and 32 percent of the placebo group). Hematologic indexes were monitored carefully, but dose modifications were rarely needed for thrombocytopenia (in 2 percent) or neutropenia (in 1 percent). The occurrence of substantial CMV illness that led to the use of ganciclovir therapy and withdrawal from the study was considered an unsatisfactory therapeutic response.
Data Analysis
The initial study design called for a total enrollment of 200 patients, with interim assessments after there were 40, 80, 120, 160, and 200 patients who could be evaluated. At the first interim analysis (of 40 patients, conducted in January 1990), the ganciclovir group had a lower incidence of CMV illness, but the difference was not statistically significant. At the second analysis (of 80 patients who had completed the protocol, conducted in July 1990), a significant difference in the rate of CMV illness was noted that favored ganciclovir, and further enrollment was stopped. By the time the second analysis was completed, 149 patients had been enrolled. Data on these 149 patients are included in this paper.
Statistical Analysis
Demographic Variables
The degree of comparability at base line between the treatment groups was examined. Difference in age was analyzed by Student's t-test. Difference in sex was analyzed by Fisher's exact test. Differences in ethnic origin and the CMV serologic status of the donor and the recipient were analyzed by Pearson's chi-square test.
Efficacy of Treatment
Analyses of the efficacy of ganciclovir treatment were based on the presence or absence of CMV illness. With regard to the presence or absence of a specific CMV illness (pneumonia, gastrointestinal tract infection, myocarditis, or CMV syndrome), the results of urine cultures for CMV, the cardiac-transplant rejection index, and the presence or absence of any type of pneumonia, the data were tested for differences between study groups by the Cochran—MantelHaenszel row mean-scores chi-square test, with stratification according to center and the recipient's serologic status. The data on the presence or absence of CMV illness were tested for differences between the ganciclovir-treated patients seropositive for CMV and those seronegative for CMV by the Cochran—MantelHaenszel row mean-scores chi-square test, with stratification according to transplant program. The time to the onset of CMV illness and the time to discharge from the hospital were analyzed for differences between treatment groups by the log-rank test.
Safety Analyses
The distributions of minimal white-cell counts, hemoglobin levels, platelet counts, and maximal serum creatinine concentrations were compared between treatment groups by Pearson's chi-square test and Fisher's exact test.
Sample
A total sample of 100 patients each in the placebo and ganciclovir groups was considered sufficient to permit detection of a treatment-related difference of 20 percent in the incidence of CMV illness with a statistical power of 0.85, by a two-sided test at the 0.05 significance level. A group sequential design8 was used to permit interim analyses after the accrual of an additional 20 patients in each group.
Methods of Analysis
All statistical tests presented here are two-sided. The actual P values are given, with significance declared at the 0.05 level. All the statistical analyses were performed with SAS, versions 5 and 6, releases 5.18 and 6.06.9
Results
One hundred forty-nine patients were enrolled in the study (76 in the ganciclovir group and 73 in the placebo group). Table 1Table 1
Base-Line Characteristics of the Study Subjects and Reasons for Premature Termination of the Study. shows the characteristics of the patients in the two groups before treatment. Age, sex, and ethnic origin were comparable, as well as the incidence of CMV seropositivity in the recipients and donors. In each group there was one case in which neither the donor nor the recipient was seropositive. The 74 patients enrolled in the study in Utah and the 75 patients enrolled at Stanford were generally comparable (data not shown). All the patients were included in the analysis of both efficacy and safety because of our plan to evaluate the results on an intention-to-treat basis.Table 1 also shows the number of patients who terminated the study early, including those who died, in each study group. There was one death each from cardiac rejection, infection, multiorgan failure, and cardiopulmonary arrest. Eighty-three percent of the ganciclovir group completed the protocol without incident, as did 70 percent of the placebo group, for an average completion rate of 77 percent. The premature terminations were due to adverse events (4 percent), death (3 percent), problems related to the administration of the study (5 percent), and unsatisfactory therapeutic responses (11 percent). No patients were lost to follow-up, but 18 percent of the placebo group, as compared with 4 percent of the ganciclovir group, terminated the study because of an apparently unsatisfactory therapeutic response — that is, the appearance of substantial CMV illness. Both groups received similar concomitant medications, except that 19 patients taking placebo (26 percent) required acyclovir to treat herpes simplex infections, as compared with 3 patients taking ganciclovir (4 percent) (P<0.001). This was not surprising, because of the known action of ganciclovir against herpes simplex.10
Table 2Table 2
Incidence of CMV Illness within 120 Days after Transplantation. shows the incidence of CMV illness within 120 days after transplantation in all the study patients and in those who were seropositive. The incidence of such illness was approximately 2 1/2 times higher in the placebo group — a statistically significant difference that led to the early termination of the study (Fig. 1Figure 1
Incidence of CMV Illness in the Two Study Groups.). A significant difference between groups was found with regard to the incidence of pneumonia, gastrointestinal tract infection, and the CMV syndrome. The degree of CMV illness ranged from mild to severe. Of the patients taking placebo, 13 of 20 (65 percent) with diagnosed organ-specific CMV illness (e.g., pneumonia, esophagitis, or gastritis) left the study. Many of these patients required rehospitalization, and all those with pneumonia and CMV illness of the gastrointestinal tract had sufficiently severe signs and symptoms to justify the use of an invasive diagnostic procedure (bronchoscopy or endoscopy). The typical signs associated with pneumonia were dyspnea and interstitial infiltrates. Patients with gastritis or esophagitis typically had ulceration with abdominal pain, bleeding, or both. No deaths were attributed to CMV illness.As shown in Tables 2 and 3Table 3
Incidence of CMV Illness within 120 Days after Transplantation, According to Institution and Serologic Status of Recipient at Study Entry., the incidence of CMV illness was related to the recipient's previous serologic status. At both study sites (Stanford and Utah) the prophylactic effect was observed only in the CMV-seropositive recipients, and not in the quarter of the patients who were CMV-seronegative before transplantation. CMV disease developed in 46 percent of the seropositive and 29 percent of the seronegative recipients of placebo (P not significant).Figure 2Figure 2
Incidence of CMV Illness in the Study Patients According to Serologic Status at Base Line and Study Group. shows the time to the development of CMV illness according to treatment group and CMV serologic status. Among the seropositive patients in whom CMV illness developed, the illness occurred a mean of 45 days after transplantation in the placebo group, as compared with 72 days in the ganciclovir group. Among the seronegative patients, those receiving placebo showed evidence of disease at an average of 56 days as compared with 71 days in those receiving ganciclovir.Ganciclovir was clearly efficacious in reducing CMV shedding (Table 4Table 4
Results of Cultures of Urine for CMV.). The incidence of CMV infection ranged from a minimum of 4 percent among the patients at entry into the study to a maximum of 56 percent in the placebo group at day 60. In contrast, 19 percent of the ganciclovir recipients had shedding of CMV at day 60. CMV was also significantly suppressed with ganciclovir treatment on day 15 and day 29 and for 30 days after ganciclovir treatment was stopped. At days 90 and 120 the excretion of CMV was similar in the two groups. To determine whether asymmetric distribution of the six patients who were culture-positive at base line had influenced the analysis of primary disease outcomes, the other 143 subjects were studied separately. Significant prevention of CMV illness with ganciclovir was still seen among those without viruria at entry (P<0.001).There was no difference between the two study groups with regard to indexes of cardiac-transplant rejection, the average time to the first discharge from the hospital (21 days), or the prevalence of anemia, neutropenia, and thrombocytopenia. Neutropenia (absolute neutrophil count, <1000×106 per liter) was seen in 5 of 76 ganciclovir recipients (7 percent) as compared with 8 of 72 placebo recipients ( 11 percent). More ganciclovir-treated patients had serum creatinine concentrations ≥220 μmol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent for the placebo group) (P = 0.024). Elevated creatinine levels were observed primarily in the first week after transplantation. They were transient (lasting three to four days), reversible, and did not lead to the termination of ganciclovir treatment in any patient. There was no difference between the placebo group and the ganciclovir group with respect to any other reported adverse events.
Discussion
Our study indicates that ganciclovir is well tolerated in heart-transplant recipients and that it can diminish both CMV excretion and the incidence of substantial CMV illness in such patients who are at high risk for CMV infection. The drug was well tolerated during the 28 days of therapy under this protocol. Ganciclovir was associated only with mild and reversible increases in serum creatinine. Careful monitoring for renal dysfunction should be undertaken to identify patients needing dose modification.
A small controlled study of ganciclovir prophylaxis in patients with cardiac transplantation was reported11 after our study was completed. It failed to show a benefit in 8 patients given the drug, but this is not surprising when one considers that our controlled study required five times as many patients in each group in order to demonstrate a beneficial effect (i.e., at the 80-patient interim analysis).
In our study there was substantial protection with ganciclovir only among the CMV-seropositive patients. There are two likely explanations for this finding. Our previous observations about the rate of virus shedding12 indicate that CMV-seropositive patients have viruria earlier than seronegative patients in whom primary infection develops after an infected heart is transplanted from a seropositive donor. In the current study, CMV disease developed approximately 11 days sooner in the seropositive recipients of placebo than in their seronegative counterparts. Therefore, since ganciclovir therapy was given only during the first 28 days, the seropositive patients were protected throughout a larger portion of their presymptomatic period of viral replication than were the seronegative recipients. Second, it is possible that ganciclovir could act with preexisting host factors, such as CMV-specific humoral and cellular immunity present in the seropositive but not the seronegative patients.
For maximal prevention of virus replication in seronegative persons, our data suggest that a longer period of ganciclovir prophylaxis is required. The combination of ganciclovir and immune globulin has been shown to treat CMV pneumonia effectively in recipients of bone marrow transplants — a result that neither therapy accomplishes alone.13 14 15 This regimen of dual therapy given over a longer period could be studied in seronegative heart-transplant recipients. It might also decrease further the severity of any CMV disease that could develop in the seropositive group.
CMV illness caused substantial morbidity, with attendant costs of treatment and diagnosis. However, no patient died of it, perhaps because those who were most seriously ill left the study to be treated with ganciclovir without the restrictions of the protocol. This trial was not designed to determine whether prophylaxis is superior to treatment with ganciclovir after CMV illness becomes apparent. We suspect, however, that prophylaxis of seropositive recipients is preferable to treatment.
Supported by a grant (AI-05629–28) from the Public Health Service and a grant from Syntex Corporation.
Source Information
From the Division of Infectious Diseases, Department of Medicine (T.C.M., S.K., S.R.), and the Department of Cardiothoracic Surgery (V.S., P.G., E.B.S.), Stanford University School of Medicine, Stanford, Calif.; the Utah Transplantation Affiliated Hospitals Cardiac Transplant Program (Departments of Medicine and Surgery at the University of Utah Medical Center, Latter-Day Saints Hospital, and the Salt Lake City Veterans Affairs Hospital), Salt Lake City (D.G.R., M.R.B., J.B.O., D.D., R.M.R., W.E.R., R.C.M.); and the Institute of Clinical Medicine and Institute for Research Data Management, Syntex Research, Palo Alto, Calif. (CD., B.D., V.S., T.C., W.B.). Address reprint requests to Dr. Merigan at the Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
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