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Research Note 337

RESEARCH NOTE positive:recipient-negative match [1], and patients undergoing anti-lymphocyte induction or rejec- tion therapy, are at greatest risk of developing CMV disease [2,3]. This study evaluated prospec- Ganciclovir prophylaxis to prevent CMV tively a targeted prophylaxis with high-dose disease in kidney recipients undergoing infrequent intravenous ganciclovir in patients anti-lymphocyte globulin treatment for treated with anti-lymphocyte globulins for acute acute rejection rejection. Michael J. Dickenmann1, Kairat Kabulbayev1, From 1994 to 2001, 51 kidney recipients at risk of Ju¨rg Steiger1, Gieri Cathomas2, CMV disease (donor and ⁄ or recipient serologically Pierre Reusser3 and Michael Tamm4 CMV-positive), who required anti-lymphocyte globulin therapy for biopsy-proven rejection, Divisions of 1Nephrology and 4Pneumology, received prophylactic intravenous ganciclovir as Department of Internal Medicine, University a single dose three times a week, for a total of nine Hospital, CH-4031 , 2Institute for doses, starting on the day of anti-rejection treat- Pathology, University Hospital, CH-4410 Liestal ment. The dose of ganciclovir was adjusted to the and 3Hoˆpital Re´gional, CH-2900 Porrentruy, creatinine clearance (Cl): Cl > 50 mL ⁄ min: 10 mg ⁄ kg; Cl 25–49 mL ⁄ min: 7.5 mg ⁄ kg; Cl 10– 24 mL ⁄ min: 5 mg ⁄ kg; Cl < 10 mL ⁄ min: 2.5 mg ⁄ kg. CMV antigenaemia was measured with the pp65 ABSTRACT assay before and every 1–2 weeks for 6 months after the acute rejection episode, as described Kidney recipients (n ¼ 51) at risk of cytomegalo- previously [4,5]. CMV infection was considered virus (CMV) disease, and requiring anti-lympho- to be present if CMV antigens were detected in cyte globulin therapy because of biopsy-proven blood leukocytes by the pp65 assay in the absence rejection, received high-dose ganciclovir, three of clinical or laboratory signs of a symptomatic times a week, for a total of nine doses. CMV CMV infection. A diagnosis of CMV disease % disease was observed in seven (14 ) patients required positive CMV detection and clinical or within 6 months. Six of these patients were in a laboratory signs of infection, including fever, leu- group of 45 CMV-seropositive recipients, and one copenia, or organ involvement (hepatitis, pneu- was in a high-risk group of CMV-seronegative monitis, colitis, gastritis, chorioretinitis), as agreed recipients. High-dose intravenous ganciclovir, three times a week, seems to be an efficient, safe internationally [6–9] Donor and recipient were % and easy way to prevent CMV disease in patients both serologically CMV-positive in 31 (61 ) cases, treated with anti-lymphocyte globulins for acute while in six (12%) cases the donor was CMV- rejection. positive and the recipient CMV-negative, and in 14 (27%) cases a CMV-positive recipient received a Keywords Cytomegalovirus, ganciclovir, kidney CMV-negative graft. In total, 39 (76%) patients transplants, rejection were treated with anti-human rabbit thymocyte Original Submission: 6 May 2003; Revised Submis- globulins (ATG), six (12%) patients with anti- sion: 11 August 2003; Accepted: 8 September 2003 human horse thymocyte globulins, and four (8%) patients with monoclonal anti-CD3 lymphocyte Clin Microbiol Infect 2004; 10: 337–339 antibodies (OKT-3). An additional two (4%) 10.1111/j.1198-743X.2004.00827.x patients were treated initially with ATG, followed by OKT-3 because of ongoing rejection. No graft Cytomegalovirus (CMV) continues to be a cause was lost as an immediate consequence of the of substantial morbidity and mortality after solid rejection episode. Of the 51 patients, 48 received organ transplantation. Patients with a donor- all nine doses of ganciclovir. One patient, treated initially with ATG, followed by OKT-3 because of resistant rejection, received 14 doses of ganciclovir. Corresponding author and reprint requests: M. Dickenmann, Ganciclovir prophylaxis was discontinued because Division of Nephrology, University Hospital, CH-4031 Basel, Switzerland of significant leucopenia in two patients, one after E-mail: [email protected] five doses, and one after eight doses.

Ó 2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 332–348 338 Clinical Microbiology and Infection, Volume 10 Number 4, April 2004

Table 1. Incidence of CMV disease Prophylactic regimen Incidence of in the present and previously pub- Number of during antibody therapy CMV disease lished studies Study patients CMV status because of acute rejection n (%)

Present study 6 Recipient– Intravenous ganciclovir 1(17%) Donor+ three times weekly (nine doses) Kletzmayr et al. [13] 18 Recipient– Intravenous ganciclovir 10 (55.5%) Donor+ every day (10–14 days)a Present study 45 Recipient+ Intravenous ganciclovir 6(13%) three times weekly (nine doses) Hibberd et al. [12] 23 Recipient+ Intravenous ganciclovir every daya 5(22%) Hibberd et al. [12] 11 Recipient+ No prophylaxis 7 (64%)

aAs long as antibodies were given.

Seven (14%) of the 51 patients developed CMV 100 disease within 6 months of anti-rejection treat- 90 ment despite ganciclovir prophylaxis (Table 1). 80

Three of these seven patients already had a 70 positive CMV anti-genaemia before the start of 60 anti-rejection treatment. The mean time from start 50 CMV infection of anti-rejection therapy to CMV disease was 40 54 days (range: 17–87 days). One patient experi- 30 enced a CMV primary infection (one of six high- 20 risk patients). In six patients, CMV reactivation 10 occurred (six of 45 patients at risk). At the CMV disease beginning of anti-rejection treatment, CMV anti- % patients with CMV infection or disease 0 1 2 3 4 5 6 genaemia was negative in 42 (82%) and already Months after start of rejection treatment positive in nine (18%) patients. Of the 42 negative Fig. 1. Cumulative number of patients developing CMV patients, 23 (55%) became CMV antigenaemia- infection or CMV disease within 6 months of rejection positive after the anti-rejection treatment despite therapy (51 patients at risk). ganciclovir prophylaxis. Four of these developed CMV disease. CMV antigenaemia was detected at intravenous ganciclovir administered only three least once in a total of 32 (63%) of the 51 patients times a week is effective in preventing CMV within 6 months of rejection treatment, while disease in patients at risk because of anti- 19 (37%) patients remained negative during the lymphocyte globulin rejection therapy. An overall entire observation period. Six (12%) of the rate of CMV disease of 14% within 6 months was 51 patients were at high risk of CMV primary observed (13% in the group of CMV-seropositive infection (i.e., donor CMV-seropositive and recipients, and 17% in the high-risk group of recipient CMV-seronegative). All of these were CMV-seronegative recipients). These data indi- CMV antigenaemia-negative when anti-rejection cate a clear benefit in comparison with a previ- therapy was started, but CMV antigenaemia was ously reported rate of CMV disease of > 60% in detected subsequently in four of these patients, patients without prophylactic treatment [2,12] and one patient developed CMV disease. The (Table 1). The results in seropositive and sero- cumulative incidence of patients developing CMV negative patients were also better in comparison infection or CMV disease is shown in Fig. 1. with previous reports that used a daily adminis- The risk of developing CMV infection or CMV tration of intravenous ganciclovir during the disease after anti-rejection treatment with steroid rejection treatment (Table 1) [12,13]. pulses and anti-lymphocyte globulins is high [10] While the regimen used in the present study To date, only two studies have investigated the was mostly successful in the prevention of CMV efficacy of targeted prophylactic daily intraven- disease, it did not prevent asymptomatic CMV ous ganciclovir therapy in CMV-seropositive kid- infection. Indeed, 55% of patients developed a ney recipients treated with anti-lymphocyte positive CMV antigenaemia as a consequence of globulins because of acute rejection [11,12]. The the anti-rejection treatment, despite ganciclovir results of the present study show that high-dose prophylaxis. This might be a consequence of the

Ó 2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 332–348 Research Note 339 infrequent dosage interval that permitted a rejection in renal transplantation. Transplantation 2001; 71: longer time of virus replication in the absence 764–767. 11. Conti DJ, Freed BM, Singh TP, Gallichio M, Gruber SA, of an adequate virus-static ganciclovir blood Lempert N. Preemptive ganciclovir therapy in cytomega- concentration. However, the goal of CMV pro- lovirus–seropositive renal transplant recipients. Arch Surg phylaxis is not to suppress CMV reactivation, 1995; 130: 1217–1221. but to avoid the development of CMV disease 12. Hibberd PL, Tolkoff-Rubin NE, Conti D et al. Preemptive until a patient’s specific T-cells are capable of ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recip- coping with the virus [5]. As ganciclovir was ients: a randomized controlled trial. Ann Intern Med 1995; administered only three times a week by a 123: 18–26. peripheral vein, outpatient treatment was poss- 13. Kletzmayr J, Kreuzwieser E, Watkins-Riedel T, Berlakov- ible. This allows cost savings and, in contrast to ich G, Kovarik J, Klauser R. Long-term oral ganciclovir prophylaxis for prevention of cytomegalovirus infection an oral virus-static therapy, is independent of and disease in cytomegalovirus high-risk renal transplant the patient’s compliance. The suggested targeted recipients. Transplantation 2000; 70: 1174–1180. prophylactic approach is efficient, safe and easy 14. Martin D, Sierra-Madero J, Walmsley S et al. A controlled to perform in an outpatient clinic setting. Future trial of valganciclovir as induction therapy for cytomega- prophylactic therapies using new oral formula- lovirus retinitis. N Engl J Med 2002; 346: 1119–1126. tions of antiviral agents [14] should be com- pared to the regimen described in the present study. RESEARCH NOTE

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Ó 2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 332–348