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Keywords:

  • Cytomegalovirus;
  • ganciclovir;
  • thymoglobulin;
  • transplantation;
  • valganciclovir

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

The clinical patterns and predictors of cytomegalovirus (CMV) disease in kidney and/or pancreas transplant patients on ganciclovir (1.0 g po t.i.d.) or valganciclovir (450 mg po q.d.) prophylaxis were studied. This is a retrospective analysis of 129 transplant recipients. Median follow up was 12 months (range, 6–18 months). The overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive). Seventeen of 18 patients were diagnosed with CMV after completion of 3 months' prophylaxis (median 8 weeks, range, 2–28 weeks). Induction treatment with thymoglobulin, and Donor +/Recipient – CMV status were the strongest predictors for the development of CMV disease. Cytomegalovirus incidence was not different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively).

Valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. High-risk individuals might require higher doses or longer duration of valganciclovir treatment.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Despite the introduction of newer antiviral medications for prophylaxis, cytomegalovirus (CMV) infection is still the most common opportunistic infection following solid organ transplantation. The incidence of symptomatic CMV infection varies between 20 and 60% after transplantation and depends on the type of immunosuppressive treatment, the antiviral prophylaxis, the CMV status of the recipient and donor, and the methods used to detect CMV infection (1,2). It is more common in patients treated with antilymphocyte antibodies, inadequate antiviral prophylaxis, or CMV seronegative recipients that receive transplants from CMV seropositive donors (1–6).

Cytomegalovirus disease significantly increases morbidity and mortality in transplant recipients, not only by severe primary infection but also by indirect effects on the allograft. Cytomegalovirus infection can initiate endothelial activation and vascular injury that may trigger acute rejection, chronic rejection, atherosclerosis, transplant glomerulopathy, or thrombotic microangiopathy (1).

Acyclovir was initially used for CMV prophylaxis, but recent clinical trials demonstrated that high-dose acyclovir is not effective in preventing CMV disease in renal transplant recipients (5,6). Valacyclovir, a prodrug of acyclovir, has a higher bioavailability and increased efficacy in CMV prophylaxis (7). Ganciclovir was the first drug proven to be effective in life-threatening CMV infection (8). Oral ganciclovir prophylaxis has decreased the incidence and severity of CMV infection in kidney and/or pancreas transplant recipients (1,2,9–11). Valganciclovir is a valine ester of oral ganciclovir and has markedly higher bioavailability as compared with ganciclovir (70 vs. 7%) (12–14). Once a day oral dosing of 450 mg of valganciclovir produces similar exposure compared with 2.5–5.0 mg/kg of intravenous ganciclovir in liver transplant recipients (12). Valganciclovir is in a Phase III trial in high-risk (D +/R –) solid organ transplant recipients, and the preliminary results were recently presented at the Annual ‘Interscience Conference on Antimicrobial Agents and Chemotherapy meeting’ (15).

The aim of this study was to investigate the incidence, time-course, and clinical patterns of CMV disease in kidney and/or pancreas transplant recipients under ganciclovir or valganciclovir prophylaxis, and to identify the risk factors for CMV disease.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Patient population and study design

We retrospectively studied all individuals who underwent kidney and/or pancreas transplantation between January 1st, 2001 and March 31st, 2002 at the Mount Sinai Medical Center. Median follow up was 12 months (range, 6–18 months)

Immunosuppression and prophylaxis

All patients received triple immunosuppression with corticosteroids, mycophenolate mofetil (MMF), and microemulsion cyclosporin or tacrolimus. Corticosteroids were initiated intraoperatively with 500 mg of methylprednisolone, followed by oral prednisone taper to 10 mg/day by 2 months, and 5.0–7.5 mg/day by 1 year after transplantation. MMF was given 1.0–1.5 g b.i.d. Microemulsion cyclosporin was started 5 mg/kg po b.i.d. and the dose was adjusted to maintain trough levels 300–350 ng/mL for the first month post-transplant, and 200–300 ng/mL thereafter. Tacrolimus was started as 0.1–0.2 mg/kg po b.i.d. and the dose was adjusted to keep trough levels 10–15 ng/mL for the first month, and 5–10 ng/mL thereafter. Patients with delayed graft function, pancreas transplantation, rapid steroid withdrawal, and high-risk patients who were defined as African-American recipients, panel reactive antibody > 20%, positive flow T and/or flow or complement dependent cytotoxicity B cell cross-match, or immunologic loss of a previous transplant received induction treatment with thymoglobulin 1.5 mg/kg for 5 days.

All patients received CMV prophylaxis post-transplant and after treatment of a rejection episode for 3 months. D –/R – patients without thymoglobulin induction treatment received acyclovir 400 mg po twice a day. All other patients received intravenous ganciclovir during initial hospitalization and 1 g po three times a day (dose adjusted for renal function) after discharge until October 30, 2001. After this period, patients received valganciclovir 450 mg po once a day. Trimethoprim/sulfamethoxazole, mycelex troches, calcium supplementation and antiulcer prophylaxis were also routinely prescribed to all patients.

CMV definition, diagnosis, and treatment

Cytomegalovirus infection was divided into noninvasive CMV disease and tissue-invasive CMV disease. Noninvasive CMV disease was defined as the documentation of CMV viremia by hybriD-capture RNA-DNA hybridization test with the clinical symptoms of fever, myalgia, malaise, leukopenia (WBC < 4000), or increased liver function tests without another explanation or evidence of tissue invasion. Tissue-invasive CMV disease was diagnosed histopathologically by the presence of CMV antigens or typical viral inclusion bodies. All patients with CMV disease were initially hospitalized and treated with 10–21 days of intravenous ganciclovir followed by a 3–4-month course of oral ganciclovir or valganciclovir.

CMV RNA-DNA hybridization test

Cytomegalovirus was studied by Murex hybrid capture system (HCS, Murex, Dartford, UK). Hybrid capture system is a signal-amplified solution hybridization antibody capture assay for the quantification of CMV DNA in whole blood.

Statistical analysis

Possible predictors of CMV disease, such as, recipient gender, age, and race; donor gender and age; source and type of transplant; type of induction treatment; CMV antibody status of the donor and recipient; acute rejection episodes; and type of prophylactic treatment for CMV, were of interest. Univariate association of each variable with CMV disease was analyzed by the chi-square test, or the chi-square test for trend, as appropriate. After significant univariate association (p-value < 0.05) was found separately, stratified tests were performed for each of the other factors having an association with the outcome by the Mantel-Haenszel or the Cochran-Armitage Exact Trent Test, as appropriate. Multiple logistic regression analysis was not performed in this study because of an insufficient number of adverse outcomes (n = 18), patients with CMV disease.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Patient characteristics

Between January 1st, 2001 and March 31st, 2002, 148 patients received kidney and/or pancreas transplants at Mount Sinai Medical Center. Nineteen patients who received CMV prophylaxis for more than 3 months or who were followed up for less than 6 months were excluded from analysis and the remaining 129 patients were included in this study. There were 81 male (63%), 48 female (37%), 98 White (76%), and 31 African-American (24%) patients. One hundred and twelve patients received kidney transplants (40 cadaver, 50 living-related, 22 living-unrelated), five combined kidney/liver, four combined kidney/pancreas, and eight pancreas after kidney transplants. Sixty patients received induction treatment with thymoglobulin, and seven with basiliximab, while 62 patients did not receive any antibody induction. In terms of CMV antibody status, 57 were Donor (D) +/Recipient (R) + (44%), 27 D –/R + (19%), 17 D +/R – (16%), and 28 D –/R – (21%). Fourteen patients received prophylaxis with acyclovir (D –/R – patients without thymoglobulin induction treatment for herpes prophylaxis), 68 ganciclovir, and 47 valganciclovir. Median follow up after transplantation was 12 months (range, 6–18 months). Fifteen patients had acute rejection episodes (12%). Only one patient was treated with OKT3 and the remainder with ‘pulse’ steroids.

CMV disease

The overall incidence of CMV disease at 1 year post-transplant was 14% (18 of 129 patients). Five patients (4%) had tissue-invasive CMV disease (three CMV colitis, one CMV gastritis, and one CMV nephritis) that was diagnosed by biopsy, and 13 (10%) had noninvasive CMV disease, as diagnosed by the blood CMV RNA-DNA hybridization test. Only one patient had noninvasive CMV disease during the initial 3-month CMV prophylaxis period. The remaining patients were diagnosed with CMV after the completion of prophylaxis, a median of 8 weeks later (range, 2–28 weeks). All patients responded to treatment. Only one patient had recurrent CMV disease 6 weeks after the completion of treatment (5.5%). We have not observed CMV resistance in our patients to date. One-year patient and graft survival rates were 100% for CMV patients.

Predictors of CMV disease

The effects of the various clinical variables on the risk of acquiring CMV disease based on univariate analysis are shown in Table 1. Induction treatment with thymoglobulin, D +/R – CMV status, African-American recipients, patients aged older than 50 years, and cadaveric donor recipients were found to have a higher risk for the development of CMV disease. Acute rejection was not associated with CMV disease. Three of 18 CMV patients (17%) had previous acute rejection episode, and 12 of 111 non-CMV patients (11%). There was also no association between CMV disease and subsequent development of acute rejection. Recipient and donor gender, and donor age were also not found to be associated with CMV disease.

Table 1.  Risk of cytomegalovirus disease for various demographic characteristics
 nCMV disease + Number (%)p-value
  • *

    No test was performed, as all pancreas transplant patients received thymoglobulin treatment.

  • **

    Statistical test was carried out with D –/R + and D +/R + combined.

  • CMV = cytomegalovirus.

Number of patients (%)12918 (14%) 
Recipient gender  NS
 Male8112 (15%) 
 Female486 (13%) 
Recipient age ≥ 50 years  0.07
 No645 (8%) 
 Yes6513 (20%) 
Recipient race  0.014
 White989 (9%) 
 African-American319 (29%) 
Donor gender  NS
 Male689 (13%) 
 Female609 (15%) 
Type of transplant  *
 Kidney11211 (10%) 
 Kidney/Pancreas42 (50%) 
 Pancreas82 (25%) 
 Kidney/Liver52 (40%) 
Source of donor organ  0.033
 Cadaver5712 (21%) 
 Living-related502 (4%) 
 Living-unrelated224 (18%) 
Induction with thymoglobulin  0.003
 No693 (4%) 
 Yes6015 (25%) 
Acute rejection  NS
 No1143 (13%) 
 Yes153 (20%) 
CMV antibody status  0.0002**
 D –/R –281 (4%) 
 D –/R +272 (7%) 
 D +/R +577 (12%) 
 D –/R –178 (47%) 
CMV prophylaxis  NS
 Acyclovir140 (0%) 
 Ganciclovir6810 (15%) 
 Valganciclovir478 (17%) 

Fifteen of 60 patients (25%) who received thymoglobulin induction treatment developed CMV disease, representing 83% of the CMV patients. This rate was significantly higher when compared with patients who received either basiliximab (none had CMV disease) or no induction treatment [only three of 62 patients (4.8%) had CMV disease] (p = 0.002). In order to see if association of induction treatment with CMV disease held up while controlling for other factors, we analyzed by stratifying separately on recipient race (p = 0.007), CMV status (p = 0.0035), source of transplant (p = 0.0044), and whether recipients were aged older than 50 years (p = 0.0002), and the Mantel-Haenszel tests revealed induction treatment to be strongly associated with CMV disease.

D +/R – patients had higher rates of CMV disease, eight of 17 patients (47%), when compared with CMV-positive recipients, nine of 84 patients (10.7%), or D –/R – patients, one of 28 patients (3.6%) (p = 0.0002). Similarly stratifying separately on recipient race (p = 0.0005), induction with thymoglobulin (p = 0.002), source of transplant (p = 0.001), and recipient age older than 50 years (p = 0.0004), by using the Cochran-Armitage exact trend tests, CMV status was found to be significantly associated with CMV disease.

Cytomegalovirus disease developed more frequently in African-Americans (AAs), patients older than 50 years of age, and cadaveric organ recipients. However, thymoglobulin induction treatment was used more frequently in these patients. If induction treatment was controlled for, while separately analyzing these three potential predictors for their association with CMV disease, only recipient age was found to be significantly associated with CMV disease (p = 0.011), but not race (p = 0.12) or source of organs (p = 0.12).

CMV prophylaxis

D –/R – patients without induction treatment received acyclovir for herpes prophylaxis and none of these 14 patients developed CMV disease. Cytomegalovirus incidence was not statistically different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively). Only one of 18 patients developed CMV during the initial 3-month prophylaxis period, indicating that ganciclovir or valganciclovir are effective during the prophylactic period. This prophylaxis was also effective in preventing CMV disease in 95% of the patients who did not receive thymoglobulin induction treatment. The incidence of leukopenia (WBC < 35 000) was similar in the patients treated with ganciclovir or valganciclovir (50 vs. 49%, respectively), and responded by decreasing the doses of MMF and/or antiviral medication. Severe (absolute neutrophil count < 500), prolonged neutropenia developed in two patients who received valganciclovir prophylaxis and persisted despite discontinuation of MMF and valganciclovir, and required Neupogen (granulocyte colony stimulating factor). None of the patients in the ganciclovir group developed severe neutropenia.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

This retrospective analysis demonstrates that the overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive) in kidney and/or pancreas transplant recipients at our center. This incidence has not changed with the introduction of valganciclovir for CMV prophylaxis. Valganciclovir has higher bioavailability compared with oral ganciclovir and was thought to further increase the efficacy of prophylactic therapy. The preliminary results of a phase III clinical trial in D +/R – solid organ recipients reported a similar incidence of CMV disease in valganciclovir- and ganciclovir-treated groups (12.1 vs. 15.2%, respectively). The similar prophylactic adequacy with the two drugs makes valganciclovir advantageous because of patient compliance, as it is taken only once daily, compared with oral ganciclovir, for which two tablets need to be taken three times daily. The dose of valganciclovir was 900 mg q.d. in this clinical trial and for HIV patients (13,15). However, the 450-mg dose of valganciclovir provides a similar plasma concentration time curve (AUC) as 1.0 g t.i.d. doses of ganciclovir in patients with creatinine clearance (CrCl) levels between 50 and 70 mL/min (11,14). We decided to use the 450-mg dose in our patients because kidney transplant recipients generally do not have a CrCl greater than 70 mL/min. Half of our valganciclovir-treated patients required the MMF and/or valganciclovir doses to be decreased or held because of neutropenia. Two of them had prolonged neutropenia requiring granulocyte colony stimulating factor. None of the patients in the ganciclovir group developed severe neutropenia. Using higher doses of valganciclovir (900 mg q.d.) might have further increased the incidence of neutropenia.

Thymoglobulin induction treatment and D +/R – CMV antibody status were the most important risk factors for CMV disease in our patients. This result indicates that our current protocol of 3 months of ganciclovir or valganciclovir prophylaxis was effective in 95% of the patients who did not receive thymoglobulin. All but one patient had CMV disease after discontinuing 3 months' prophylaxis treatment, indicating the effectiveness of ganciclovir or valganciclovir during the prophylactic period. These results indicated that thymoglobulin-treated and/or D +/R – recipients require higher doses or longer duration of valganciclovir treatment. Recently, we increased the duration of prophylaxis in thymoglobulin-treated patients to 6 months, and we have not observed CMV resistance in our patients to date. However, concerns remain about the possibility of inducing CMV resistance, or untoward effects of the medication, such as bone marrow suppression. Ganciclovir resistance has been mainly reported in HIV-positive patients. A few recent studies have documented increased ganciclovir resistance in solid organ transplant recipients (16,17). Drug resistance is most prevalent in D +/R – transplant recipients with prolonged ganciclovir exposure. Pre-emptive treatment could help to decrease the emerging resistance of CMV (8). It is still controversial whether prophylactic or pre-emptive therapy is the optimal strategy for preventing CMV disease (18,19). Pre-emptive therapy minimizes drug exposure and decreases the prevalence of resistance. Prophylactic treatment has the benefit of decreasing not only CMV disease incidence, but also indirect CMV effects, including rejection, as well as preventing infection by other herpes viruses. Unfortunately, we do not have enough pharmacologic options to eradicate CMV in transplant recipients, and effective and safe vaccination is not available. Prophylactic treatment with CMV immunglobulin has been shown to reduce the severity of the disease but did not prevent infection (1).

Cytomegalovirus disease recurrence after successful treatment of the initial episode has emerged as an important problem in recent reports, with rates varying between 20 and 50% (1,20). Only one patient had recurrence of CMV in our study group. The difference from our results could be because of acyclovir treatment for CMV after initial intravenous ganciclovir in previous reports (14), or the duration of treatment. Our patients received at least 3 months of ganciclovir or valganciclovir after initial intravenous ganciclovir treatment.

In summary, this retrospective study emphasizes that valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. It prevents invasive CMV disease during prophylaxis in all patients and 95% of nonthymoglobulin-treated patients even after prophylaxis during a 1-year follow-up period. However, CMV disease continues to be prevalent in organ transplant recipients, among those who had received thymoglobulin induction treatment, and seronegative recipients of seropositive donors, despite the introduction of valganciclovir. These patients might require higher doses or longer duration of valganciclovir treatment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  • 1
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  • 2
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