Comparative study of prophylactic oral ganciclovir and valacyclovir in high-risk kidney transplant recipients

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1 Nephrol Dial Transplant (2003) 18: DOI: /ndt/gfg039 Original Article Comparative study of prophylactic oral ganciclovir and valacyclovir in high-risk kidney transplant recipients Angelito Yango 1,2, Paul Morrissey 2, Abdurahman Zanabli 1, James Beaulieu 3, Douglas Shemin 1, Lance Dworkin 1, Anthony Monaco 2 and Reginald Gohh 1,2 1 Division of Renal Diseases, Department of Medicine, 2 Division of Organ Transplantation, Department of Surgery, Rhode Island Hospital, Brown University School of Medicine and 3 Department of Pharmacy Services, Rhode Island Hospital, Providence, RI, USA Abstract Background. Cytomegalovirus (CMV) is a major pathogen in renal transplant patients causing significant post-transplant morbidity and mortality. Prophylactic antiviral therapy, currently implemented in most kidney transplant centres, has significantly reduced the incidence of CMV infection after transplantation. Oral ganciclovir has been shown to be an effective prophylactic agent in preventing CMV disease and infection with a demonstrated superior efficacy over oral acyclovir., a prodrug of acyclovir with a higher level of bioavailability than acyclovir, has also been shown to be effective in preventing CMV disease when given as prophylactic treatment. Methods. In a retrospective analysis of 150 renal transplant recipients in our centre, we compared the efficacy of oral ganciclovir with valacyclovir in preventing CMV infection. Seventy-seven consecutive renal transplant recipients prophylactically treated with oral ganciclovir for 12 weeks after transplant were compared with 73 consecutive recipients treated with oral valacylovir for an equal length of time. Results. No difference was noted in the incidence of CMV infection between the two treatment groups (5.1 vs 5.4%) after a 6 month follow-up. Likewise, the incidence of acute rejection was similar in both groups (11.6 vs 6.8%). All cases of CMV infection occurred in high-risk patients (donor positiveurecipient negative). Conclusion. The prophylactic use of oral valacylovir is as effective as oral ganciclovir in reducing CMV infection and disease after kidney transplantation. Correspondence and offprint requests to: Reginald Y. Gohh, MD, Division of Renal Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. rgohh@lifespan.org Keywords: cytomegalovirus; ganciclovir; kidney transplantation; prophylaxis; treatment; valacyclovir Introduction Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality in organ transplantation, occurring in ;20 60% of all renal transplant recipients [1,2]. Disease manifestations range in severity from a mild febrile syndrome to multi-organ involvement, typically occurring within the first 6 months after transplantation [3]. Furthermore, there is indirect evidence that CMV infection itself is an independent risk factor for acute and chronic allograft rejection [4]. Seronegative recipients of kidneys from seropositive donors are at greatest risk. Other risk factors for CMV infection include a history of blood transfusions, the use of anti-lymphocyte antibody preparations and the so-called net state of immunosuppression. The availability of various antiviral drugs used prophylactically for CMV infection has significantly reduced the incidence of primary and secondary infections in renal transplant recipients when administered during the early period after transplantation. Ganciclovir, when given orally for 3 months after transplantation, has previously been shown superior to oral acyclovir for CMV prophylaxis, particularly for recipients of seropositive donor kidneys [5,6]. Recently, valacyclovir, a prodrug of acyclovir, has also been shown in a randomized, placebo-controlled, double-blinded trial to be safe and effective in preventing CMV disease after transplantation [7]. We conducted a retrospective analysis comparing two groups of patients treated prophylactically with either oral ganciclovir or oral valacyclovir for 12 weeks in preventing CMV disease after kidney transplantation. No industry financial support was solicited to underwrite the cost of conducting this study. # 2003 European Renal Association European Dialysis and Transplant Association

2 810 A. Yango et al. Table 1. Doses of antiviral agents according to renal function Serum creatinine (mgudl) Ganciclovir Dialysis dependent 1.5 g q.d. 500 mg q.d. ) g t.i.d mg q.d g q.i.d mg b.i.d g q.i.d mg t.i.d. detection of CMV immunoglobulin M (IgM), or CMV detection by PCR. In several patients, locally invasive CMV disease was diagnosed on biopsy specimens. Patients diagnosed with CMV disease had their antiviral prophylaxis discontinued and were administered a minimum 2 week course of intravenous ganciclovir. Thereafter, patients were placed back on their respective antiviral therapies (ganciclovir or valacyclovir) for an additional 4 8 weeks. Subjects and methods Patients Seventy-seven consecutive patients who underwent kidney transplantation at Rhode Island Hospital from January 1998 to May 1999 received CMV prophylaxis with oral ganciclovir (1 g p.o. t.i.d.) for 12 weeks (group 1). This group was compared with 73 consecutive kidney transplant recipients from June 1999 to August 2000 who received CMV prophylaxis with oral valacyclovir (2 g p.o. q.i.d.) for 12 weeks (group 2). Each group was followed for 6 months for evidence of CMV disease, with diagnosis based on positive CMV polymerase chain reaction (PCR), shell vial culture or serological conversion in symptomatic individuals. CMV status was determined pre-transplant by enzyme immunoassay. Prophylaxis was initiated within 24 h after transplantation and continued for 12 weeks. All patients received intravenous ganciclovir (2.5 mgukguday) during the duration of anti-lymphocyte antibody induction therapy or for 4 days following transplantation if no induction therapy was utilized. Thereafter, patients were started on either oral ganciclovir or valacyclovir. Doses of either agent were adjusted according to renal function (Table 1). The primary efficacy endpoint was an episode of CMV infection anduor disease occurring within the first 6 months after transplantation. Immunosuppression All kidney transplant recipients received calcineurin inhibitor-based immunosuppression of microemulsion cyclosporine or tacrolimus, mycophenolate mofetil and prednisone. Induction with anti-lymphocyte antibody was initiated in the setting of delayed graft function, recipients of marginal donor kidneys, or those individuals who were highly sensitized [panel reactive antibodies (PRA) )20%]. Patients receiving cyclosporine received ketoconazole (200 mguday) as antifungal prophylaxis and to reduce cyclosporine requirements. Patients treated with tacrolimus did not receive ketoconazole but did receive clotrimazole troches as antifungal prophylaxis. Trimethoprimusulfamethoxazole (97%) or pentamidine (3%) was used for Pneumocystis carinii prophylaxis. CMV definition CMV disease was presumed based on the presence of fever unexplained by ongoing bacterial infection and accompanied by any or all of the following signs: leukopenia (white blood cell counts 4000umm 3 or less), thrombocytopaenia (platelet counts umm 3 or less) or a persistent viral syndrome (myalgias, arthralgias and fatigue). CMV disease was confirmed based on a positive shell vial culture assay, Statistical analysis Results are expressed as mean"sem. Student s t-test was used to assess differences in patient characteristics and outcomes between the two treatment groups. A two-sided P-value of was considered to be statistically significant. Results Patient characteristics Table 2 provides the demographic characteristics of the two treatment groups. There were no statistically significant differences between the two groups with respect to age, gender, transplant number, donor source, aetiology of end-stage renal disease and donorurecipient (DuR) CMV status. Although only Table 2. Baseline patient characteristics Ganciclovir N Age (mean"sd) 43.9" "13.8 Gender Male Female Aetiology (%) DM 21 (28.7) 23 (29.8) GN 15 (20.5) 13 (16.8) Htn 11 (15.0) 9 (11.6) Others 26 (35.6) 34 (41.5) Donor source (%) Cadaver 39 (53.4) 39 (50.6) Living 34 (46.5) 38 (49.3) Transplant number First Re-transplant 3 3 PRA (%) 6.2" "19.8 Induction treatment (%) 39 (53.4%) 38 (49.3%) Primary immunosuppression InductionqCyA-based immunosuppression InductionqTac-based 11 9 immunosuppression Inductionqothers a 2 0 CyA-based immunosuppression Tac-based immunosuppression 2 5 Others b 0 1 CMV DuR status (%) DquRq 43 (58.9) 42 (54) DquR 6 (8.2) 9 (11.6) D urq 18 (24.6) 21 (27.2) D ur 6 (8.2) 5 (6.4) CyA, cyclosporine A; Tac, tacrolimus. a Mycophenolate mofetilqprednisone. b Azathioprineqprednisone.

3 Comparative study of prophylactic oral ganciclovir and valacyclovir Table 3. CMV disease at 6 months according to DuR CMV serology at transplant (ns73) Ganciclovir (ns77) DquRq a 3u43 (6.9%) 3u42 (7%) NS DquR 1u6 (16%) 1u9 (11%) NS D urq 0u18 0u21 NS D ur 0u6 0u5 NS Total b 4u73 (5.4%) 4u77 (5.1%) Time to develop CMV 0 3 months 0 1 NS 3 6 months 4 3 NS a Number of episodesunumber of patients in each DuR CMV serology subgroup. b Total number of CMV disease episodes in each treatment group. available for recipients of cadaver allografts, pretransplant PRA levels were no different between the two groups. Use of induction therapy, primarily with polyclonal anti-lymphocyte antibody preparations, was similar in both groups. There were no significant differences in maintenance immunosuppressive regimens, which consisted primarily of calcineurin inhibitor-based therapy of either cyclosporine A microemulsion or tacrolimus. CMV diseases rates The rates of symptomatic CMV disease were similar in both groups of patients (Table 3 and Figure 1). Within the 6 month follow-up period, there were four cases of CMV disease in both groups of patients prophylactically treated with either oral ganciclovir or valacyclovir. When stratified according to DuR CMV status prior to transplantation, CMV disease in both groups occurred only in high-risk patients (i.e. P DquRq and DquR pairs). In the ganciclovir prophylaxis arm, three active cases occurred in the DquRq subgroup and one in the DquR subgroup. Only one case was found during the ganciclovir prophylactic window in the DquRq subgroup. Similarly, in the valacyclovir prophylaxis group, three cases of CMV disease occurred in the DquRq subgroup and one in the DquR category. None of the CMV disease occurred during the valacyclovir prophylactic period. Both drugs were well tolerated with only a single patient in the ganciclovir group discontinuing therapy due to leukopenia. This patient remained CMV-disease free for the duration of the scheduled follow-up. All cases of confirmed CMV disease were treated successfully (defined as a remission of symptoms) with a 2 week course of intravenous ganciclovir followed by a repeat 4 8 week prophylactic course of either valacyclovir or ganciclovir. Acute rejection There were more episodes of biopsy-proven acute rejection in the ganciclovir-treated arm than in the valacyclovir-treated group [9 (11.7%) vs 5 (6.8%)] during the follow-up period, although this difference did not reach a statistical significance. Of the nine patients who developed acute rejection in the ganciclovir-treated group, only one had a prior episode of CMV disease. Of the five patients who developed acute rejection in the valacyclovir-treated group, one also had a prior episode of CMV disease. All rejections were successfully treated with a course of pulse corticosteroid therapy. Renal function was no different between the two treatment arms at the end of the treatment period. The mean serum creatinine of the ganciclovir group was 1.6"0.5 mg% compared with 1.5"0.5 mg% in the valacyclovir arm (PsNS). 811 Fig. 1. Six month incidence and time course of CMV disease in the two treatment groups ganciclovir (GC) vs valacyclovir (VC). The 6 month incidence of CMV disease is not significantly different between the two treatment groups (Ps0.9).

4 812 A. Yango et al. Table 4. Pharmacokinetic profiles of valacyclovir and acyclovir [18 20] Discussion CMV infection and disease remain a major cause of morbidity and mortality among renal transplant recipients, particularly during the first 6 months after transplantation when the degree of immunosuppression is at its peak [4]. These events can have significant detrimental effects on both allograft function and survival [5]. The major risk factors for the development of CMV disease include the serological status of both donor and recipient before transplantation as well as the relative degree of immunosuppression. CMV seronegative recipients of kidneys from seropositive hosts are at the highest risk with transmission rates in the order of %. In CMV seropositive recipients of seropositive donor kidneys, the rate of secondary infection may be as high as 20% [6,8]. Furthermore, the use of anti-lymphocyte antibody agents, as either induction or anti-rejection therapy, also significantly increases the risk of CMV infection [9]. Numerous prophylactic treatments designed to prevent CMV disease have been studied, including highdose acyclovir, oral ganciclovir and, more recently, oral valacyclovir [6,7,10]. Oral ganciclovir has been shown in a randomized, prospective-controlled trial to be superior to acyclovir in preventing CMV disease in high-risk kidney transplant recipients [5]. Although generally well tolerated, acyclovir has a low oral bioavailability even in high doses and a relatively low in vitro efficacy against CMV, thus accounting for its limited efficacy as a prophylactic agent [11]. Recently, valacyclovir, the L-valyl ester prodrug of acyclovir, has been shown in a randomized, placebo-controlled trial to be efficacious in preventing CMV disease after renal transplantation. In this study, Lowance et al. [7] demonstrated that a 90-day prophylactic course of oral valacylovir significantly reduced the incidence of CMV disease in both seronegative and seropositive kidney transplant recipients. Stimulated by these promising results, we retrospectively compared the efficacy of oral ganciclovir and valacyclovir in preventing CMV disease in a series of 150 consecutive adult kidney transplant recipients. Between January 1998 and May 1999, a 12 week course of oral ganciclovir (1 g t.i.d.) was routinely used for CMV prophylaxis. Beginning on July 1999, oral valacyclovir (2 g q.i.d.) was used for CMV prophylaxis. Retrospective analysis of our data showed no significant difference in the rate of CMV within the first 6 months after transplantation. Both groups were similar in age, gender, aetiology of renal failure and type and number of kidney transplants. Since the DuR CMV serological status and the use of anti-lymphocyte antibody therapy have been shown to be risk factors for developing CMV disease, these variables were also compared in the two treatment groups. The rate of anti-lymphocyte antibody use was not significantly different between the ganciclovir and valacyclovir treatment arms (49.3 vs 53.4%, Ps0.50). Furthermore, there were no statistical differences in the number of serologically Acyclovir Bioavailabilty (%) AUC (humcguml) T 1u2 (h) Renal clearance (mluminu1.73 m 2 ) high-risk DuR pairs (DquRq, DquR ) between the two groups. Our results are similar to those found by other authors showing significant reduction in the incidence of CMV disease with the use of antiviral prophylaxis. Brennan et al. [12] showed that an initial 12 week course of oral ganciclovir resulted in a 40% reduction in the incidence of CMV disease compared with deferred therapy. The severity of CMV disease likewise is significantly reduced with ganciclovir prophyalaxis compared with limited prophylaxis only during antirejection therapy with monoclonal or polyclonal antibodies [6]. Similarly, Lowance et al. [7] showed that a 3 month prophylactic course with valacyclovir significantly reduced the incidence of CMV disease in high-risk kidney transplant patients. Our retrospective study is the first to compare and show equivalent efficacy of valacylovir and ganciclovir in reducing CMV disease after kidney transplantation. Although we did not attempt to score for disease severity, there was no apparent difference in either group, as all cases responded well to treatment. Since valacyclovir is simply the prodrug of acyclovir, our results would seem to contradict the results of a previously reported study by Flechner et al. [5] that demonstrated the superiority of ganciclovir over acyclovir in CMV prophylaxis in renal transplant recipients. This may be accounted for by the superior pharmacokinetic profile of valacyclovir when compared with its parent drug (Table 4). Although valacyclovir disappears rapidly from plasma, this is due to its rapid metabolic conversion to acyclovir, resulting in very high plasma concentrations of the latter. With oral valacyclovir, plasma acyclovir levels are three to five times higher than those achievable with an equivalent dose of oral acyclovir [13]. Furthermore, the relative underdosing of acyclovir may also have contributed to the inefficiency of acyclovir in the previous study. The daily dose of valacyclovir in our study was 8 guday compared with 3.6 guday of acyclovir given as a prophylaxis treatment in the study by Flechner et al. [5]. This would seem to suggest that acyclovir is not a less effective drug if given on an equivalent drug exposure basis. Although not statistically significant, rejection episodes in the valacyclovir-treated group were less than that in the ganciclovir-treated arm. Whether this is directly related to the protective effects against CMV infection or a direct adjunctive immunosuppressive quality of valacyclovir cannot be concluded based on our limited data. Interestingly, a recent meta-analysis

5 Comparative study of prophylactic oral ganciclovir and valacyclovir on the use of other anti-cmv prophylactic agents did not show an associated reduction in the risk of acute rejection [14]. Both drugs were well tolerated by our patients. One individual in the ganciclovir-treated arm had to be discontinued following the development of significant but reversible leukopenia, while none of the patients in the valacyclovir-treated group had to be discontinued due to side effects. Although previous studies have indicated that acyclovir may impact on GFR directly [15], there were no differences in serum creatinines when comparing the two groups. Given the demonstrated equal efficacy and safety of both drugs, valacyclovir appears to provide an ideal alternative to ganciclovir for CMV prophylaxis after kidney transplantation. Although no ganciclovirresistant strains were encountered in our series, there have been recent concerns about the emergence of such species in solid organ transplant recipients [16, 17]. With the use of valacyclovir for CMV prophylaxis, ganciclovir may then be reserved for treatment of CMV disease, thus minimizing the emergence of ganciclovir-resistant strains. Another clear advantage of valacyclovir over ganciclovir is its cost savings. Currently, a 3 month course of valacyclovir at our institution is $2000 less than the same course of ganciclovir. In conclusion, treatment with valacyclovir as CMV prophylaxis for 90 days is as equally efficacious and safe as oral ganciclovir in preventing CMV disease. is also associated with lower rates of acute rejection and offers a significant cost advantage over ganciclovir, particularly for the moderate- to high-risk renal transplant recipient. References 1. Farrugia E, Schwab TR. 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