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P T. 2010 December; 35(12): 676–679.
PMCID: PMC3008374

Efficacy and Safety of a Lower-Dose Valganciclovir (Valcyte) Regimen for Cytomegalovirus Prophylaxis In Kidney and Pancreas Transplant Recipients

Vrinda Bhat, PharmD, Megan McIntyre, PharmD, and Tracey Meyers, PharmD

Abstract

Purpose:

We evaluated the efficacy and safety of the current cytomegalovirus (CMV) prophylaxis regimen used at Virginia Mason Medical Center in Seattle.

Methods:

A single-center, retrospective analysis was conducted in a regional renal transplantation center at a tertiary teaching facility.

Study population:

Seventy patients who underwent kidney and/or pancreas transplantation from October 2006 through December 2008 were observed for a period of six months after the procedure. Transplant recipients at risk for developing CMV disease received valganciclovir 450 mg daily.

Results:

Outcome measures were incidence of CMV disease and incidence of severe leukopenia during the six-month postoperative period. Of 70 patients, seven (10%) developed CMV disease and five (7.1%) developed severe leukopenia while taking valganciclovir. Based on donor (D) and recipient (R) CMV serostatus, the incidence of CMV disease and severe leukopenia incidence was highest in the D+/R– group. Severe leukopenia developed in one patient with CMV disease who had a D+/R–kidney transplant. No statistical calculations were performed.

Conclusion:

The current lower-dose valganciclovir regimen at our institution was found to be efficacious and safe, and it provided significant cost savings.

BACKGROUND

Cytomegalovirus (CMV) prophylaxis guidelines recommend a 900-mg daily dose of valganciclovir (Valcyte, Roche/Genentech) to prevent CMV disease in solid-organ transplant recipients.1 Recent clinical trials indicate that a dose of 450 mg daily provides effective CMV prophylaxis.2,3

The standard practice at Virginia Mason Medical Center is to prescribe six months of valganciclovir 450 mg daily for CMV prophylaxis in kidney and pancreas transplant recipients. This lower dosing regimen is based on recommendations from the center’s P&T committee review of the drug’s efficacy and safety in order to avoid neutropenia toxicity and to reduce medication expenditures (written communication, P&T Guidelines, September 2001). The objective of our study was to evaluate the effectiveness of the current CMV prophylaxis regimen used at Virginia Mason Medical Center.

METHODS

Study Design

We conducted a single-center, retrospective analysis at a 336-bed tertiary academic medical center. Virginia Mason Medical Center is a regional transplantation center, with an average of 90 to 100 transplant procedures performed per year. We used the center’s electronic medical records (PowerChart; Cerner Corp., Kansas City, Mo.) to identify patients who underwent kidney or pancreas transplantation, or both, at the center from October 2006 through December 2008.

Patients were included in the analysis if they were concurrently receiving immunosuppressive therapy and prophylactic valganciclovir and were observed for a follow-up period of six months after the procedure. Initially, 217 patients were eligible to receive valganciclovir, regardless of the dose or indication. Of those patients, 147 were excluded based on the following criteria:

  • Seventy-eight patients did not have a documented follow-up visit or laboratory work at the end of the six-month prophylaxis period.
  • Twenty-two patients were taking valganciclovir for reasons other than post-transplant prophylaxis.
  • Twelve patients were undergoing a repeated transplantation procedure.
  • Eleven patients were on a nonstandard prophylaxis protocol.
  • Eight patients were scheduled for a pancreas-after-kidney transplantation operation.
  • Eight non-transplant patients were using valganciclovir for CMV treatment.
  • Four patients were using valganciclovir for reasons other than kidney and/or pancreas transplantation.
  • Four patients did not complete the prophylaxis course because of unrelated organ rejection or death.

Patients who underwent a repeated transplantation procedure or pancreas-after-kidney transplantation were excluded because of the potentially unknown or higher risk of developing CMV (Figure 1). The 70 patients included in the study were observed for at least six months after transplantation, which marked the end of the valganciclovir prophylaxis period.

Figure 1
Inclusion and exclusion criteria for patient enrollment in a retrospective analysis of valganciclovir used as immunosuppressive therapy.

Data Collection

We analyzed the data to identify those patients who developed CMV disease and severe leukopenia while receiving prophylactic valganciclovir. Data collection included the date and type of transplant; the CMV serostatus of the donor (D) and recipient (R); the patient’s age, sex, and date of the last clinic visit; the duration of valganciclovir prophylaxis; the CMV incidence, and the incidence of severe leukopenia.

Patients with normal renal function, defined as a creatinine clearance (CrCl) of 50 mL/minute or more, received valganciclovir 450 mg daily; patients with renal insufficiency (CrCL, 25 to 49 mL/minute) received valganciclovir 450 mg every other day. In this evaluation, we did not assess dose adjustments based on renal function and did not perform any statistical calculations.

RESULTS

Patient Demographics

Of the 70 patients who were included in the study (22 women, 48 men), 63 had kidney transplants, one had a pancreas transplant, and six had simultaneous pancreas and kidney transplants. The CMV serostatus of donors and recipients prior to the procedure was obtained from patient charts. Of the 70 patients, 29 (41.4%) were D+/R+, 17 (24.3%) were D+/R–, 14 (20%) were D–/R+, and 10 (14.3%) were D–/R– (Table 1).

Table 1
Baseline Characteristics of Transplant Patients Receiving a Prophylactic Regimen For Cytomegalovirus (CMV) Disease

Patients’ ages ranged from 26 to 76 years (mean age, 53 years; median age, 55 years) (see Figure 1).

Induction Regimen and Immunosuppression

At Virginia Mason Medical Center, kidney and/or pancreas transplant recipients receive an induction regimen. More than 90% of these patients receive a total of five doses of intravenous (IV) antithymocyte globulin 1.5 mg/kg (a polyclonal antibody) on days 0, 2, 4, 6, and 8. The remaining patients who are considered to be at low risk receive a total of two doses of IV daclizumab sterile concentrate for injection (Zenapax, Roche) 1 mg/kg (an interleukin-2 [IL-2] receptor monoclonal antibody) on days 0 and 14. (Daclizumab is no longer on the market.)

Recipients are considered to be at low risk if they have a 0% panel-reactive antibody (PRA) and if they receive a kidney, a pancreas, or both, from a living donor. In addition, patients subsequently receive mycophenolate mofetil (Cell-Cept, Roche) 2 g/day in divided doses, tacrolimus (e.g., Prograf, Astellas/Fujisawa), and steroids as an immunosuppressive regimen after transplantation. A study by Weng et al. showed no correlation between induction therapy and CMV disease.4

Cytomegalovirus Disease

CMV active infection is defined as the detection of virus replication via nucleic acid–based assays or antigenemia studies. CMV disease is defined as evidence of CMV infection with attributable symptoms; it can be further classified as viral syndrome and tissue-invasive disease.5

The incidence of CMV during the six-month prophylaxis period was obtained from clinical notes and CMV quantitative polymerase chain reaction (PCR) testing. The overall incidence of CMV disease was seven of 70 patients (10%), with the highest incidence in the D+/R– group, and this is consistent with similar published studies (Figure 2).68 Of these seven patients, four developed viral syndrome and three developed tissue-invasive disease (Table 2). Patients who developed viral syndrome were treated in the outpatient setting; patients who developed tissue-invasive disease required hospitalization.

Figure 2
Incidence of cytomegalovirus (CMV) disease after six months of therapy with valganciclovir 450 mg daily. VMMC = Virginia Mason Medical Center. (Data from Akalin E, et al. Am J Transplant 2004;4:148–149;6 Luan FL, et al. J Am Soc Nephrol 2009;20:2449–2458; ...
Table 2
Incidence of Cytomegalovirus (CMV) Disease And Severe Leukopenia in Transplant Recipients During a Six-Month Prophylaxis Period

CMV occurred in six patients who completed valganciclovir prophylaxis within their first year after transplantation. CMV developed in these patients between 28 and 92 days after they discontinued valganciclovir (mean incidence, 59 days; median incidence, 54 days).

Severe Leukopenia

Severe leukopenia was defined as a white blood cell (WBC) count of fewer than 1,600 cells/mm3. We obtained the incidence of this illness from laboratory results during the six-month prophylactic period. Based on this definition, five of 70 patients (7.1%) developed severe leukopenia while using valganciclovir, with the highest incidence in the D+/R– group. Severe leukopenia occurred in these patients between 53 and 162 days after the transplantation procedure (mean incidence, 106 days; median incidence, 89 days). One patient with CMV disease who had a D+/R– kidney transplant developed severe leukopenia (see Table 2). Those patients who developed severe leukopenia were each treated with at least one 6-mg dose of subcutaneous (SQ) pegfilgrastim (Neulasta, Amgen).

Cost Savings

Cost savings were associated with the reduced medication expense of valganciclovir 450 mg daily when compared to valganciclovir 900 mg daily for six months of CMV prophylaxis. All patients who developed severe leukopenia were treated with a minimum of one dose of SQ pegfilgrastim 6 mg. Because more patients would be expected to develop severe leukopenia with valganciclovir 900 mg daily than with the 450-mg daily dose, there would be additional savings by avoiding the cost of pegfilgrastim. The savings noted in Table 3 are an estimate of how much patients would save if they paid for these medications out of pocket.

Table 3
Cost Savings Achieved with a Reduced Dosing Regimen Of Valganciclovir (Valcyte) in Cytomegalovirus Prophylaxis

STUDY LIMITATIONS

Our evaluation had some limitations because of its retrospective, non-controlled design. CMV–PCR testing, duration of prophylaxis, and guidelines for D–/R– patients were not standardized; furthermore, we did not exclude D–/R–patients from the study.

We did not assess patient compliance, actual out-of-pocket costs, or third-party payer expenses. The cost savings associated with the lower-dose valganciclovir regimen could be diminished if they resulted in higher CMV rates requiring treatment, compared with the higher-dose valganciclovir regimen.

We restricted our data collection to patient information that was available in our center’s electronic medical records. Many of our institution’s transplant patients intermittently received some follow-up care at outside facilities. About 70% of our transplant patients are referred from outside the western Washington area and intermittently receive some follow-up care at outside facilities. Assuming that the outside facilities did not deviate from our medical center’s protocol, similar results would be expected. However, many patients who were observed at outside facilities were excluded from the study because of the lack of follow-up data available at Virginia Mason Medical Center.

Finally, we could not adequately evaluate neutropenia because of sparse and incomplete data in our center’s electronic medical records.

Future steps include evaluating the benefits and risks of using a higher-dose valganciclovir regimen for those patients at the greatest risk of CMV disease. Our center needs to determine whether treating severe leukopenia, which can occur with the higher dose, would be more cost effective than treating CMV disease that might ensue with the lower dose.

We recommend that the Medical Center also develop CMV prophylaxis guidelines for D–/R– patients because prophylaxis regimens were not consistent in this patient population. Owing to the existence of conflicting evidence, further research needs to be conducted to determine the appropriate valganciclovir dosing and duration for CMV prophylaxis.

CONCLUSION

When kidney and pancreas transplant recipients received valganciclovir 450 mg daily for six months, the overall incidence of CMV disease was 10% and the incidence of severe leukopenia was 7.1%. Patients with CMV D+/R– serostatus had the highest rate of CMV disease (57.1%), which is expected, because this group has the highest risk of the disease. Our evaluation results were consistent with those of similar published studies (see Figure 2), and they also accomplished the goal of the valganciclovir guidelines of Virginia Mason Medical Center’s P&T committee. The current lower-dose valganciclovir regimen at our institution was efficacious and safe, and provided significant cost savings by reducing medication expenditures and by obviating the need for severe leukopenia treatment.

Acknowledgments

The authors would like to thank Cyrus Cryst, MD, FASN, for providing support and clinical guidance during this evaluation.

Footnotes

Disclosure: The authors report no commercial or financial conflicts in relation to this article.

REFERENCES

1. Cytomegalovirus. Guidelines for the prevention and management of infectious complications of solid organ transplantation. Am J Transplant. 2004;4(Suppl. 10):51–58.
2. Chamberlain CE, Penzak SR, Alfaro RM, et al. Pharmacokinetics of low and maintenance dose valganciclovir in kidney transplant recipients. Am J Transplant. 2008;8:1297–1302. [PMC free article] [PubMed]
3. Brum S, Nolasco F, Sousa J, et al. Leukopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil. Transplant Proc. 2008;40:752–754. [PubMed]
4. Weng FL, Patel AM, Wanchoo R, et al. Oral ganciclovir versus low-dose valganciclovir for prevention of cytomegalovirus disease in recipients of kidney and pancreas transplants. Transplantation. 2007;83(3):290–296. [PubMed]
5. Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6(2):262–274. [PubMed]
6. Akalin E, Bromberg JS, Sehgal V, et al. Decreased incidence of cytomegalovirus infection in thymoglobulin-treated transplant patients with 6 months of valganciclovir prophylaxis. Am J Transplant. 2004;4:148–149. [PubMed]
7. Luan FL, Stuckey LJ, Park JM, et al. Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection. J Am Soc Nephrol. 2009;20:2449–2458. [PubMed]
8. Gabardi S, Magee CC, Baroletti SA, et al. Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: A single-center, retrospective analysis. Pharmacotherapy. 2004;24:1323–1330. [PubMed]

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