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Effective oral ganciclovir prophylaxis against cytomegalovirus disease in heart transplant recipients
Effective Oral Ganciclovir Prophylaxis Against Cytomegalovirus Disease in Heart Transplant Recipients G.M. Mullen, M.A. Silver, K. Malinowska, C.E. Lawless, R.C. Lichtenberg, P.C. Barath, P.J. O’Keefe, J.A. Robinson, and V. Yeldandi
C
YTOMEGALOVIRUS DISEASE is defined as a clinical syndrome characterized by fever, leukopenia, or organ dysfunction associated with positive CMV blood culture, tissue cultures, or demonstration of CMV in tissue by histologic criteria. CMVD causes additional hospitalizations, morbidity, and mortality in heart transplant recipients.1–3 CMVD is also associated with the long-term development of accelerated arteriosclerosis in heart transplant recipients.4 –5 The risk for developing this opportunistic infection in the heart transplant recipient relates to either reactivation of latent infection following remote exposure, transmission through donor organ or blood products, and the net state of immunosuppression.6 However, even in the recipient with prior immunity to CMV due to remote exposure, superinfection with a new and different CMV strain can occur.7–9 The persistent clinical problem of CMVD has prompted development of numerous strategies for preventing this opportunistic infection in the heart transplant recipients through technically impeccable surgery, precisely managed immunosuppression, careful screening and prevention of exposure (eg, using CMV-negative blood products), and the use of preventive antimicrobial strategies. A particular emphasis of these preventive antimicrobial strategies has been to administer various antiviral agents for the first 4 to 6 months after orthotopic heart transplant, when CMV infections are more prevalent, possibly due to enhanced immunosuppression during this time.10 –18 Our goal was to decrease the mortality, morbidity, and rehospitalizations from CMVD by administering a prolonged course of a possibly more effective (but also more expensive) anti-CMV agent: oral ganciclovir (PO G) instead of oral acyclovir (PO A). Therefore, we substituted the newly available G (an analog of A) during the early posttransplant period in hopes of decreasing CMVD in our patients.19 METHODS Patient Population This study involved the retrospective analysis of data collected on 165 heart transplanted patients at Loyola University Heart Transplant Program. Beginning on September 1, 1992, we initiated a CMVD prevention protocol utilizing intravenous (IV) G for 14
days followed by PO A for 90 days. This experience with heart transplant patients comprises group I. However, the persistent problem of CMVD after orthotopic heart transplantation prompted us to use the newly available oral form of G (in place of the oral A). This more recent experience with heart transplant comprises group II. Both groups received induction with IV G 5 mg/kg body weight twice daily. The A dosage was 800 mg PO thrice daily and PO G was prescribed at 1000 mg thrice daily. G dosage was adjusted over the treatment period if needed due to neutropenia or nausea or renal insufficiency. Not included in this analysis are 26 patients who did not receive G either because they were thought to be at low-risk for developing CMVD based on donor/recipient CMV serology (ie, donor negative/recipient negative for CMV antibody) or because they died within a few days of orthotopic heart transplantation and never received G. The subsequent analyses are based on the remaining 139 patients, 77 in group I and 62 in group II.
Data Analysis Patients were categorized into risk groups according to donor and recipient CMV serology. Descriptive statistics and independent t tests were performed to assess patient demographic information. Fisher exact test (Chi-square distribution test) was performed to evaluate a difference in number of CMVD cases in both groups.
RESULTS
Table 1 provides the demographic information on the heart transplant recipients involved in this study. There were 77 heart transplant recipients who received CMV prophylaxis per our former protocol (sequentially 14 days of IV G followed by 90 days of PO A) and these patients comprise group I. Another 62 patients who received our more recent CMV prophylactic regimen (sequentially 14 days of IV G followed by 90 days of PO G) comprise group II. Patient gender distribution was similar; 22 (28.6%) female and 55 (71.4%) male in group I versus 15 (22.4%) female and 47 (77.6%) male in group II. Also, their age distribution was similar, with a mean of 49.8 years and standard deviation of From Loyola University Health System, Department of Medicine/Division of Cardiology, Heart Transplant Program, Maywood, Illinois. Address reprint requests to G. Martin Mullen, MD, Loyola University Health System, Heart Transplant and Heart Failure Program, Maywood, IL 60153.
0041-1345/98/$19.00 PII S0041-1345(98)01361-X
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4110
Transplantation Proceedings, 30, 4110–4112 (1998)
EFFECT OF GANCICLOVIR PROPHYLAXIS ON CYTOMEGALOVIRUS
4111
Table 1. Patient Demographic Information Group
I
II
N Sex Female Male Age (years) Mean 6 STDEV Range
77
62
22 (28.6%) 55 (71.4%)
15 (22.4%) 47 (77.6%)
49.8 6 11.8 20 – 68
P
52.2 6 12.4 16 – 69
,.01 ,.03 NS
11.8 with a range of 20 to 68 years at the time of the heart transplant in group I versus a mean of 52.2 years and standard deviation of 12.4 with a range of 16 to 69 years at the time of the heart transplant in group II. Table 2 provides the proportions of CMVD cases in the 6 months following heart transplantation in both groups broken down into risk categories according to donor/ recipient serology. There is no significant difference in these proportions among the risk categories. However, the total number of CMVD cases, 14 (19%) in group I versus 1 (2%) in group II, was significantly different (P , .01). Figure 1 represents a percentage distribution of CMVD cases in both groups in the first 6 months posttransplant. Only one patient in group II developed CMVD in the first two quarters posttransplantation. The average time of onset of the CMVD was 4.82 6 3.94 months in group I versus 8.62 6 5.78 months in group II. Patient survival in group I was slightly lower, 87% and 86% versus 94% and 92% in group II both in the first 6 and 12 months posttransplant, respectively.
DISCUSSION
The data clearly show that sequential use of IV G for 14 days followed by PO G for 90 days is much more effective Table 2. Distribution of Cytomegalovirus Disease versus Cytomegalovirus Serology During the First 6 Months After Heart Transplant Group
Cytomegalovirus Serology D1/R1 D1/R2 D2/R1 D2/R2 Total Cytomegalovirus Serology D1/R1 D1/R2 D2/R1 D2/R2 Total Cytomegalovirus Disease cases
I
II
P
N (%) 24 (31) 14 (18) 30 (39) 9 (12) 77
N (%) 19 (30) 14 (23) 18 (29) 11 (18) 62
NS NS NS NS 1
CMVD (%) 9 (38) 2 (14) 2 (7) 1 (11)
CMVD (%) 1 (5) 0 (0) 0 (0) 0 (0)
,.01 NS NS NS
14 (18)
1 (2)
,.01
Fig 1. A percentage distribution of cytomegalovirus disease cases in both groups during the first 6 months after heart transplantation.
prophylaxis for CMVD after heart transplantation than use of IV G for 14 days followed by PO A for 90 days. The IV/PO G regimen reduced the number of CMVD cases drastically during the first 6 months after heart transplant (from 18% in group I to 2% in group II). Most impressive is the fact that the IV/PO G regimen delayed the onset of CMVD for over 6 months, beyond the period of the most intense immunosuppression and generally the time of highest succeptibility to opportunistic infections including CMV. With this new prophylaxis regimen, the distribution of the CMVD cases does not appear to be related to donor/recipient serology as observed previously.7,16 In our experience one CMVD case occured in the medium risk group (ie, donor positive/recipient positive). We are now evaluating whether high risk cases such as donor positive/ recipient negative should receive an even more prolonged PO G regimen, perhaps at modified dosages to prevent side effects. Although our regimens, old and new, seem to be similar, they are obviously different in that PO G seems to be much more effective. In terms of economics, PO G treatment at first glance seems more expensive. Based on the current pharmacy prices, for a patient weighing 70 kg the first 2 weeks of IV G prophylaxis was estimated to be $4791, a cost shared by patients in both groups. However, the subsequent 3-month course of PO A is estimated to be only $137, whereas the 3-month course of PO G is $3,000, a much more costly alternative. Nonetheless, we feel that the reduction of the number of the hospital days due to CMVD by PO G probably more than offsets its increased costs. Regarding patient survival, there were no deaths directly related to CMVD in either group, but there was a trend toward better survival in the PO G group. Whether longterm survival will be better after eliminating CMVD in terms of subsequent allograft arteriopathy remains to be seen. Nonetheless, the fact that the survival rate at 6 months was better in group II reassures us that further investigation with PO G is warranted.
4112
SUMMARY
The presented data show the combined sequential use of IV G for 14 days followed by PO G for 90 days is a much more effective prophylaxis for CMVD after heart transplantation than use of IV G for 14 days followed by PO A for 90 days. A need for hospitalization due to CMVD is significantly reduced by this new strategy. The follow-up in group II is shorter than in group I but is now at least 6 months in group II, without any new cases in the first 6 months after cardiac transplantation. Some currently unknown adverse effect of prolonged PO G, which may be present, is not identified in this analysis. ACKNOWLEDGMENT The authors gratefully acknowledge Mr. Jack Corliss for his assistance with statistical analyses.
REFERENCES 1. Kirklin JK, Naftel DC, Levine TB, et al: J Heart Lung Transplant 13:394, 1994 2. Laske A, Gallino A, Mohacsi P, et al: Transplant Proc 23:1170, 1991 3. Steel HM, Murday AJ: Transplantation 62:492, 1996 4. Koshinen P, Lemstrom K, Mattila S, et al: Clin Transplant 10:487, 1996
MULLEN, SILVER, MALINOWSKA ET AL 5. Wu TC, Hruban RH, Ambinder RF, et al: Am J Pathol 140:739, 1992 6. Thaler SJ, Rubin RH: Curr Opinion Cardiol 11:191, 1996 7. Bailey TC, Trulock EP, Storch GA, et al: N Engl J Med 327:891, 1993 8. Grossi P, Revello MG, Mioli L, et al: J Heart Lung Transplant 9:712, 1990 9. Wreghitt T: J Antimicro Chemo 23 (suppl):E49, 1989 10. Cooper DK, Novitzky D, Schlegel V, et al: J Heart Lung Transplant 10:656, 1992 11. Gajarski RJ, Rosenbaltt HM, Denfield SW, et al: Texas Heart Inst J 24:97, 1997 12. Soghikian MV, Valentine VG, Berry GJ, et al: J Heart Lung Transplant 15:881, 1996 13. MacDonald PS, Keogh AM, Marsham D, et al: J Heart Lung Transplant 14:32, 1995 14. Wagner JA, Ross H, Hunt S, et al: Transplantation 60:1473, 1995 15. Lowry RW, Adam E, Hu C, et al: J Heart Lung Transplant 13:122, 1994 16. Merigan TC, Renlund DG, Keay S, et al: N Engl J Med 326:1182, 1992 17. Steinhoff G, Behrend M, Wagner TOF, et al: J Heart Lung Transplant 10:9, 1991 18. Eisenmann D, Knipp H, Laube H, et al: Transplant Proc 2:2322, 1990 19. Crumpacker CS: N Engl J Med 335:721, 1996
C
YTOMEGALOVIRUS DISEASE is defined as a clinical syndrome characterized by fever, leukopenia, or organ dysfunction associated with positive CMV blood culture, tissue cultures, or demonstration of CMV in tissue by histologic criteria. CMVD causes additional hospitalizations, morbidity, and mortality in heart transplant recipients.1–3 CMVD is also associated with the long-term development of accelerated arteriosclerosis in heart transplant recipients.4 –5 The risk for developing this opportunistic infection in the heart transplant recipient relates to either reactivation of latent infection following remote exposure, transmission through donor organ or blood products, and the net state of immunosuppression.6 However, even in the recipient with prior immunity to CMV due to remote exposure, superinfection with a new and different CMV strain can occur.7–9 The persistent clinical problem of CMVD has prompted development of numerous strategies for preventing this opportunistic infection in the heart transplant recipients through technically impeccable surgery, precisely managed immunosuppression, careful screening and prevention of exposure (eg, using CMV-negative blood products), and the use of preventive antimicrobial strategies. A particular emphasis of these preventive antimicrobial strategies has been to administer various antiviral agents for the first 4 to 6 months after orthotopic heart transplant, when CMV infections are more prevalent, possibly due to enhanced immunosuppression during this time.10 –18 Our goal was to decrease the mortality, morbidity, and rehospitalizations from CMVD by administering a prolonged course of a possibly more effective (but also more expensive) anti-CMV agent: oral ganciclovir (PO G) instead of oral acyclovir (PO A). Therefore, we substituted the newly available G (an analog of A) during the early posttransplant period in hopes of decreasing CMVD in our patients.19 METHODS Patient Population This study involved the retrospective analysis of data collected on 165 heart transplanted patients at Loyola University Heart Transplant Program. Beginning on September 1, 1992, we initiated a CMVD prevention protocol utilizing intravenous (IV) G for 14
days followed by PO A for 90 days. This experience with heart transplant patients comprises group I. However, the persistent problem of CMVD after orthotopic heart transplantation prompted us to use the newly available oral form of G (in place of the oral A). This more recent experience with heart transplant comprises group II. Both groups received induction with IV G 5 mg/kg body weight twice daily. The A dosage was 800 mg PO thrice daily and PO G was prescribed at 1000 mg thrice daily. G dosage was adjusted over the treatment period if needed due to neutropenia or nausea or renal insufficiency. Not included in this analysis are 26 patients who did not receive G either because they were thought to be at low-risk for developing CMVD based on donor/recipient CMV serology (ie, donor negative/recipient negative for CMV antibody) or because they died within a few days of orthotopic heart transplantation and never received G. The subsequent analyses are based on the remaining 139 patients, 77 in group I and 62 in group II.
Data Analysis Patients were categorized into risk groups according to donor and recipient CMV serology. Descriptive statistics and independent t tests were performed to assess patient demographic information. Fisher exact test (Chi-square distribution test) was performed to evaluate a difference in number of CMVD cases in both groups.
RESULTS
Table 1 provides the demographic information on the heart transplant recipients involved in this study. There were 77 heart transplant recipients who received CMV prophylaxis per our former protocol (sequentially 14 days of IV G followed by 90 days of PO A) and these patients comprise group I. Another 62 patients who received our more recent CMV prophylactic regimen (sequentially 14 days of IV G followed by 90 days of PO G) comprise group II. Patient gender distribution was similar; 22 (28.6%) female and 55 (71.4%) male in group I versus 15 (22.4%) female and 47 (77.6%) male in group II. Also, their age distribution was similar, with a mean of 49.8 years and standard deviation of From Loyola University Health System, Department of Medicine/Division of Cardiology, Heart Transplant Program, Maywood, Illinois. Address reprint requests to G. Martin Mullen, MD, Loyola University Health System, Heart Transplant and Heart Failure Program, Maywood, IL 60153.
0041-1345/98/$19.00 PII S0041-1345(98)01361-X
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4110
Transplantation Proceedings, 30, 4110–4112 (1998)
EFFECT OF GANCICLOVIR PROPHYLAXIS ON CYTOMEGALOVIRUS
4111
Table 1. Patient Demographic Information Group
I
II
N Sex Female Male Age (years) Mean 6 STDEV Range
77
62
22 (28.6%) 55 (71.4%)
15 (22.4%) 47 (77.6%)
49.8 6 11.8 20 – 68
P
52.2 6 12.4 16 – 69
,.01 ,.03 NS
11.8 with a range of 20 to 68 years at the time of the heart transplant in group I versus a mean of 52.2 years and standard deviation of 12.4 with a range of 16 to 69 years at the time of the heart transplant in group II. Table 2 provides the proportions of CMVD cases in the 6 months following heart transplantation in both groups broken down into risk categories according to donor/ recipient serology. There is no significant difference in these proportions among the risk categories. However, the total number of CMVD cases, 14 (19%) in group I versus 1 (2%) in group II, was significantly different (P , .01). Figure 1 represents a percentage distribution of CMVD cases in both groups in the first 6 months posttransplant. Only one patient in group II developed CMVD in the first two quarters posttransplantation. The average time of onset of the CMVD was 4.82 6 3.94 months in group I versus 8.62 6 5.78 months in group II. Patient survival in group I was slightly lower, 87% and 86% versus 94% and 92% in group II both in the first 6 and 12 months posttransplant, respectively.
DISCUSSION
The data clearly show that sequential use of IV G for 14 days followed by PO G for 90 days is much more effective Table 2. Distribution of Cytomegalovirus Disease versus Cytomegalovirus Serology During the First 6 Months After Heart Transplant Group
Cytomegalovirus Serology D1/R1 D1/R2 D2/R1 D2/R2 Total Cytomegalovirus Serology D1/R1 D1/R2 D2/R1 D2/R2 Total Cytomegalovirus Disease cases
I
II
P
N (%) 24 (31) 14 (18) 30 (39) 9 (12) 77
N (%) 19 (30) 14 (23) 18 (29) 11 (18) 62
NS NS NS NS 1
CMVD (%) 9 (38) 2 (14) 2 (7) 1 (11)
CMVD (%) 1 (5) 0 (0) 0 (0) 0 (0)
,.01 NS NS NS
14 (18)
1 (2)
,.01
Fig 1. A percentage distribution of cytomegalovirus disease cases in both groups during the first 6 months after heart transplantation.
prophylaxis for CMVD after heart transplantation than use of IV G for 14 days followed by PO A for 90 days. The IV/PO G regimen reduced the number of CMVD cases drastically during the first 6 months after heart transplant (from 18% in group I to 2% in group II). Most impressive is the fact that the IV/PO G regimen delayed the onset of CMVD for over 6 months, beyond the period of the most intense immunosuppression and generally the time of highest succeptibility to opportunistic infections including CMV. With this new prophylaxis regimen, the distribution of the CMVD cases does not appear to be related to donor/recipient serology as observed previously.7,16 In our experience one CMVD case occured in the medium risk group (ie, donor positive/recipient positive). We are now evaluating whether high risk cases such as donor positive/ recipient negative should receive an even more prolonged PO G regimen, perhaps at modified dosages to prevent side effects. Although our regimens, old and new, seem to be similar, they are obviously different in that PO G seems to be much more effective. In terms of economics, PO G treatment at first glance seems more expensive. Based on the current pharmacy prices, for a patient weighing 70 kg the first 2 weeks of IV G prophylaxis was estimated to be $4791, a cost shared by patients in both groups. However, the subsequent 3-month course of PO A is estimated to be only $137, whereas the 3-month course of PO G is $3,000, a much more costly alternative. Nonetheless, we feel that the reduction of the number of the hospital days due to CMVD by PO G probably more than offsets its increased costs. Regarding patient survival, there were no deaths directly related to CMVD in either group, but there was a trend toward better survival in the PO G group. Whether longterm survival will be better after eliminating CMVD in terms of subsequent allograft arteriopathy remains to be seen. Nonetheless, the fact that the survival rate at 6 months was better in group II reassures us that further investigation with PO G is warranted.
4112
SUMMARY
The presented data show the combined sequential use of IV G for 14 days followed by PO G for 90 days is a much more effective prophylaxis for CMVD after heart transplantation than use of IV G for 14 days followed by PO A for 90 days. A need for hospitalization due to CMVD is significantly reduced by this new strategy. The follow-up in group II is shorter than in group I but is now at least 6 months in group II, without any new cases in the first 6 months after cardiac transplantation. Some currently unknown adverse effect of prolonged PO G, which may be present, is not identified in this analysis. ACKNOWLEDGMENT The authors gratefully acknowledge Mr. Jack Corliss for his assistance with statistical analyses.
REFERENCES 1. Kirklin JK, Naftel DC, Levine TB, et al: J Heart Lung Transplant 13:394, 1994 2. Laske A, Gallino A, Mohacsi P, et al: Transplant Proc 23:1170, 1991 3. Steel HM, Murday AJ: Transplantation 62:492, 1996 4. Koshinen P, Lemstrom K, Mattila S, et al: Clin Transplant 10:487, 1996
MULLEN, SILVER, MALINOWSKA ET AL 5. Wu TC, Hruban RH, Ambinder RF, et al: Am J Pathol 140:739, 1992 6. Thaler SJ, Rubin RH: Curr Opinion Cardiol 11:191, 1996 7. Bailey TC, Trulock EP, Storch GA, et al: N Engl J Med 327:891, 1993 8. Grossi P, Revello MG, Mioli L, et al: J Heart Lung Transplant 9:712, 1990 9. Wreghitt T: J Antimicro Chemo 23 (suppl):E49, 1989 10. Cooper DK, Novitzky D, Schlegel V, et al: J Heart Lung Transplant 10:656, 1992 11. Gajarski RJ, Rosenbaltt HM, Denfield SW, et al: Texas Heart Inst J 24:97, 1997 12. Soghikian MV, Valentine VG, Berry GJ, et al: J Heart Lung Transplant 15:881, 1996 13. MacDonald PS, Keogh AM, Marsham D, et al: J Heart Lung Transplant 14:32, 1995 14. Wagner JA, Ross H, Hunt S, et al: Transplantation 60:1473, 1995 15. Lowry RW, Adam E, Hu C, et al: J Heart Lung Transplant 13:122, 1994 16. Merigan TC, Renlund DG, Keay S, et al: N Engl J Med 326:1182, 1992 17. Steinhoff G, Behrend M, Wagner TOF, et al: J Heart Lung Transplant 10:9, 1991 18. Eisenmann D, Knipp H, Laube H, et al: Transplant Proc 2:2322, 1990 19. Crumpacker CS: N Engl J Med 335:721, 1996