Efficacy and Safety of Valganciclovir vs. Oral Ganciclovir for Prevention of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Authors


*Corresponding author: Carlos Paya, paya@lilly.com and paya@mayo.edu

Abstract

We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p = 0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.

Introduction

Cytomegalovirus (CMV), the most common viral infection after solid organ transplant (SOT) (1), causes significant morbidity and mortality. It can result in CMV pneumonitis, hepatitis, encephalitis and gastrointestinal disease, as well as many less serious but clinically problematic events such as fever and neutropenia (2). Furthermore, CMV has been shown to be associated with a number of indirect effects in SOT recipients including reduced long-term patient survival, increased risks of opportunistic infections, allograft dysfunction, acute and chronic graft rejection, and increased total costs (3,4). Without prophylaxis, most CMV disease occurs during the first 3 months post-transplant, when patients are receiving intensive immunosuppressive agents for prevention of graft rejection (5,6). SOT patients at highest risk are seronegative recipients of organs from seropositive donors (CMV D+/R-) (2,7,8), and those on highly immunosuppressive regimens.

Antiviral agents have proved successful for prevention of CMV infection and disease in SOT recipients (9). While originally intravenous (i.v.) ganciclovir was the mainstay, effective for both CMV prevention and treatment (10–12), more recently an oral ganciclovir formulation has been used. While this has proved effective in preventing CMV disease in SOT transplant recipients, including high-risk D+/R- patients (13–15), it has a low bioavailability (about 6–10%), and a total of 3 g, administered as 12 capsules/day in a three times a day (t.i.d.) regimen, is needed to deliver plasma ganciclovir exposures 40–50% of that achieved with the standard 5 mg/kg dose of i.v. ganciclovir (16,17). This low bioavailability limits the degree of viral suppression that can be achieved (18), and thus may predispose to emergence of resistance (19).

Valganciclovir, a valine ester pro-drug of ganciclovir, was developed to overcome the limitations of oral and i.v. ganciclovir, with a single once-daily 900 mg oral dose providing comparable plasma ganciclovir exposures to those achieved with 5 mg/kg i.v. ganciclovir (16). At 60%, its bioavailability is up to 10-fold higher than that of oral ganciclovir (16). There is already extensive clinical experience with valganciclovir in AIDS patients, where it has proved as effective as i.v. ganciclovir in treating newly diagnosed CMV retinitis (20). We therefore conducted a prospective, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of valganciclovir compared with oral ganciclovir for prevention of CMV disease in high-risk (CMV D+/R-) SOT recipients.

Materials and Methods

The study was conducted at 57 centers (US, n = 35; Canada, n = 5; Europe, n = 11; Australia/New Zealand, n = 6) and was approved by the Independent Ethics Committees/Institutional Review Boards of participating centers. It was conducted in accordance with the Declaration of Helsinki and all patients provided written informed consent. The study was performed under the supervision of an independent Drug Safety Monitoring Board.

Patients

Eligible patients were ≥13 years of age with adequate hematological and renal function receiving a first heart, liver, kidney, kidney-pancreas, kidney-heart or kidney-liver allograft or second kidney allograft, with a CMV serostatus of D+/R-. Exclusion criteria included: history of CMV infection or disease, anti-CMV therapy within the past 30 d, severe, uncontrolled diarrhea or evidence of malabsorption.

Study design

This was a double-blind, double-dummy clinical study. Patients enrolled at each study center were stratified by allograft type [heart, liver (including liver-kidney), kidney or kidney-pancreas] and randomly assigned in a 2:1 ratio at each study center to receive valganciclovir 900 mg once daily or oral ganciclovir 1000 mg t.i.d. Treatment randomization numbers were assigned by telephone via a central randomization center. The patient numbers were allocated sequentially at each study center in the order in which patients were enrolled. Patients received four ganciclovir 250 mg (Cymevene®/Cytovene®; F Hoffmann-La Roche Ltd, Basel, Switzerland) or matching placebo capsules t.i.d. and two valganciclovir 450 mg (Valcyte®; F Hoffmann-La Roche Ltd) or matching placebo tablets once daily. Treatment began within 10 d post-transplant (as soon as the patient was able to take oral medication) and continued through day 100 post-transplant. In patients with impaired renal function, dose was adjusted according to calculated creatinine clearance (21) (Table 1). Dose adjustments were also made in cases of suspected toxicity related to study drug (e.g. for hematological abnormalities). Immunosuppression was given according to the standard practice at the study centre and regimens were variable between centres. However, immunosuppressive regimens were well balanced between the two arms of the study.

Table 1.  Dosing adjustments based on creatinine clearance
Creatinine clearance*
(mL/min)
Ganciclovir
(250 mg capsules)
Valganciclovir
(450 mg tablets)
  1. *Creatinine clearance was calculated using the Cockcroft–Gault formula.

≥704 capsules t.i.d.2 tablets once daily
60 < 702 capsules t.i.d.2 tablets once daily
50 < 602 capsules t.i.d.1 tablet once daily
40 < 504 capsules once daily1 tablet once daily
25 < 404 capsules once daily1 tablet every other day
10 < 252 capsules once daily1 tablet twice weekly
<10 or patientInterrupt treatment with study drug 
on dialysisTreat with i.v. ganciclovir (0.625 mg/kg three times per week) or open label oral ganciclovir (500 mg three times per week) after hemodialysis 

Assessments

Patients were assessed at screening, first day of study drug administration, and post-transplant days 14, 28, 42, 56, 70, 84 and 100, and months 4, 4.5, 5, 6, 8, 10 and 12. Patients were monitored for signs and symptoms of CMV disease, treatment for CMV disease, opportunistic infections, acute rejection episodes and graft survival through to month 12. All adverse events were monitored, by questioning, through month 6 and drug-related adverse events through month 12. Plasma CMV load was assessed using the Cobas Amplicor CMV Monitor® Test (Roche Diagnostics, Branchburg, NJ, USA) in blood samples obtained at the time-points specified above and at onset of suspected CMV disease. Systemic exposure to ganciclovir (from either valganciclovir or oral ganciclovir) was measured from samples obtained on day 28 or 42 and day 70 or 84, based on the collection of sparse plasma samples during the treatment phase. In total, 449 plasma profiles were deduced from 242 patients (160 valganciclovir, 82 ganciclovir), using three time-points per profile (1–3 h, 5–12 h and ∼24 h post-dose). CMV viremia was determined locally at each study center, and also centrally (LabCorp: North Carolina, USA or Mechelen, Belgium) using an Federal Drug Administration (FDA)-approved or fully validated DNA/RNA-based method as previously described (22,23). CMV disease diagnosis required a positive central laboratory result.

Efficacy

The primary efficacy variable was the proportion of patients developing CMV disease (CMV syndrome and/or tissue-invasive CMV) during the first 6 months post-transplantation, as adjudicated by an independent (of both sponsor and study) blinded Endpoint Committee (medically qualified individuals with expertise in CMV infection in transplant recipients). The Committee identified CMV disease (and its onset) based on the protocol definition of CMV disease and assessment of available patient data. CMV disease incidence was also calculated according to: (a) events meeting the protocol definition of CMV disease, without Endpoint Committee adjudication (All Signs, Symptoms and Laboratory criteria fulfilled analysis) and (b) investigator-treated CMV disease events (investigator-treated analysis, regardless of protocol definition of CMV disease). The incidence of CMV disease up to12 months post-transplant was also assessed.

Secondary efficacy variables included time to CMV disease, incidence of CMV viremia, incidence of acute graft rejection, acute graft rejection after CMV disease, and graft loss, up to 12 months post-transplant.

Definition of CMV disease

CMV syndrome was defined as CMV viremia with fever ≥38 °C on ≥two occasions ≥24 h apart within a 7-d period, positive central laboratory results for CMV, and at least one of the following: new or increased malaise, two successive measurements of leucopenia (defined as a white blood cell count of <3500/μL or a white blood cell count decrease of 20% if the cell count prior to the development of clinical symptoms was <4000/μL) ≥24 h apart, atypical lymphocytosis ≥5%, thrombocytopenia, or elevation of hepatic transaminases to ≥twice the upper limit of normal (nonliver transplant recipients). Tissue-invasive CMV was defined as symptoms or signs of organ dysfunction (excluding acute rejection in the grafted organ) and evidence of localized CMV infection in a biopsy or other appropriate specimen.

Statistical analyses

We estimated that 372 patients would provide ≥90% power to demonstrate noninferiority (a delta of –0.05) (24) of the proportion of patients who developed CMV disease up to 6 months post-transplant in valganciclovir vs. ganciclovir groups [assuming the true proportion of patients in the intent-to-treat (ITT) population developing CMV disease would be 12% (25) with ganciclovir and 5% with valganciclovir].

The ITT population was the primary efficacy analysis population and comprised all D+/R- randomized patients. A per-protocol (PP) population was defined which excluded major protocol violators. The safety population included all patients who were randomized, had received at least one dose of study medication and had at least one safety assessment. The primary analysis and hypothesis testing was conducted on the 6 month data. Analyses at 12 months were secondary and no formal hypothesis testing is presented, although 95% confidence intervals (CIs) for the difference in proportions (ganciclovir-valganciclovir) were calculated. Time-to-event data are graphically displayed using a Kaplan–Meier analysis.

Results

Patients

Between April 2000 and August 2001, 372 patients were randomized to treatment (Figure 1), and had completed the study period (or died or withdrew prior to the 12-month visit) by August 19, 2002. The ITT population comprised 364 patients (8 patients who were not D+/R- were excluded): 239 in the valganciclovir arm (118 liver, 81 kidney, 35 heart, 5 kidney-pancreas) and 125 in the ganciclovir arm (59 liver 39 kidney, 21 heart, 6 kidney-pancreas). The safety analysis included 370 patients (1 patient in each group did not receive study medication). The PP population comprised 299 patients (73 excluded, mostly due to receipt of protocol-prohibited anti-CMV medications).

Figure 1.

Patient disposition during the trial.

Demographic data are presented in Table 2. Treatment groups were comparable with respect to sex, race, age, weight, height, creatinine clearance, overall degree of histocompatibility (HLA, blood group and rhesus antigens) and immunosuppression between donor and recipient. Allograft types included: 185 liver (including 2 liver-kidney transplants), 120 kidney (the number of kidneys was capped at 120), 11 kidney-pancreas and 56 heart. The proportion of patients receiving valganciclovir or ganciclovir in each allograft type was consistent with the 2:1 allocation. Duration of anti-CMV study drug prophylaxis was comparable between groups (median 97 days in each group); most patients (82% valganciclovir, 79% ganciclovir) received 91–100 days' treatment. In total, 329 patients (valganciclovir, n = 216; ganciclovir, n = 113) had complete follow-up to 12-months post-transplant.

Table 2.  Baseline demographic data for valganciclovir and oral ganciclovir treatment groups (all patients)
 Valganciclovir
(n = 245)
Ganciclovir
(n = 127)
  1. *Creatinine clearance was calculated using the Cockcroft–Gault formula. ‘Not done’ means not done within 5 d of start of study treatment.

Age, mean (years)45.745.3
Gender: male/female, no. (%) of patients179/66 (73%/27%)95/32 (75%/25%)
Race, no. (%) of patients
 Caucasian218 (89%)115 (91%)
 Black16 (6.5%)7 (6%)
 Other11 (4.5%)5 (4%)
Weight, mean (kg)81.284.2
Height, mean (cm)172.5172.7
Mean creatinine clearance* no. (%) of patients  
 <40 mL/min53 (21.6%)27 (21.3%)
 40–70 mL/min64 (26.1%)31 (24.4%)
 >70 mL/min126 (51.4%)67 (52.8%)
Not done2 (0.8%)2 (1.6%)

Efficacy

By 6 months, 12.1% of valganciclovir recipients and 15.2% of ganciclovir recipients developed CMV disease (Table 3A) as assessed by the Endpoint Committee. The difference in proportions between groups was 0.034 (95% CI, –0.042, 0.110); however, a statistically significant interaction between treatment and organ type was observed (p = 0.017). The incidence of Endpoint Committee-defined CMV disease in valganciclovir and ganciclovir groups by organ type was 19% and 12% in liver recipients, 6% and 23% for kidney, 6% and 10% for heart and 0% and 17% for kidney-pancreas patients, respectively. For the PP population, 14.9% of valganciclovir recipients and 18.1% of ganciclovir recipients developed CMV disease and the difference in proportions between groups was 0.039 (95% CI, –0.051, 0.129). By 12 months, the incidence of Endpoint Committee-defined CMV disease in valganciclovir and ganciclovir groups was 17.2% and 18.4%, respectively (difference in proportion 0.015; 95% CI, –0.068, 0.098). Only four cases of CMV disease (0.8% valganciclovir, 1.6% ganciclovir) occurred during the first 100 d post-transplant (Figure 2A).

Table 3.  (A) Summary of cytomegalovirus (CMV) disease up to 6 and 12 months post-transplant in the intent-to-treat (ITT) population, as assessed by the Endpoint Committee (data are cumulative, i.e. events up to 12 months post-transplant include the events up to 6 months). (B) Summary of cytomegalovirus (CMV) disease up to 6 and 12 months post-transplant [intent-to-treat (ITT) population]
 Percentage (no.) of patients
 Valganciclovir (n = 239)Ganciclovir (n = 125)
(A)6 months12 months6 months12 months
CMV disease*12.1% (29)17.2% (41)15.2% (19)18.4% (23)
CMV syndrome5.0% (12)7.9% (19)10.4% (13)12.0% (15)
Tissue-invasive7.1% (17)9.2% (22)4.8% (6)6.4% (8)
 Hepatitis6612
 Pneumonia2312
 Gastrointestinal tract disease121745
 Other1100
Patients inevaluable5.0% (12)9.2% (22)5.6% (7)9.6% (12)
 
*95% CI difference in proportions (–0.042, 0.110 at 6 months and –0.068, 0.098 at 12 months).
 Percentage (no.) of patients

(B) CMV disease*
Valganciclovir
(n = 239)
Ganciclovir
(n = 125)
 
  1. *All Signs, Symptoms and Laboratory criteria fulfilled (i.e. strict protocol definition of CMV disease).

Endpoint Committee
 6 months12.1% (29)15.2% (19) 
 12 months17.2% (41)18.4% (23) 
ASSL*
 6 months11.3% (27)12.8% (16) 
 12 months15.1% (36)15.2% (19) 
Investigator-treated CMV disease events
 6 months23.0% (55)21.6% (27) 
 12 months30.5% (73)28.0% (35) 
Figure 2.

Time (days) to cytomegalovirus (CMV) disease (A) as assessed by the Endpoint Committee and (B) in investigator-treated CMV disease events up to 12 months post-transplant in patients receiving antiviral prophylaxis with valganciclovir 900 mg once daily or oral ganciclovir 1000 mg 3 times daily for 100 days post-transplant [intent-to-treat (ITT) population].

By 6 and 12 months, the proportion of patients who were treated for CMV disease by the investigator was comparable in both treatment arms (valganciclovir 23.0%, ganciclovir 21.6% and valganciclovir 30.5%, ganciclovir 28.0%, respectively; Figure 2B; Table 3B). The two groups were comparable with regard to the incidence of CMV disease at both 6 and 12 months in the All Signs, Symptoms and Laboratory criteria fulfilled (Table 3B).

Virology

For patients actually receiving assigned study drug during the treatment phase, the incidence of CMV viremia above the limit of quantification (>400 copies/mL) was significantly lower with valganciclovir than ganciclovir (2.5% vs. 10.4%; p = 0.001), but was comparable between the two groups by 6 months (39.7% valganciclovir vs. 43.2% ganciclovir) and 12 months (48.5% valganciclovir vs. 48.8% ganciclovir) (Figure 3). The median time to viremia was slightly shorter in the ganciclovir arm than the valganciclovir arm (282 vs. 357 d). There was a trend towards reduced peak viral loads at the time of suspected CMV disease for patients receiving valganciclovir compared with patients receiving oral ganciclovir (Table 4). Peak viral loads were generally higher for patients experiencing CMV disease compared with patients who remained symptom free (mean 34 000 vs. 8000 copies/mL, respectively, both arms combined); however, the range of viral loads was wide and similar for the two groups(400–100 000 copies/mL for both).

Figure 3.

Time (days) to first cytomegalovirus (CMV) viral load above the level of quantification up to 12 months post-transplant in patients receiving antiviral prophylaxis with valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times daily for 100 days post-transplant [intent-to-treat (ITT) population].

Table 4.  Summary of peak cytomegalovirus (CMV) viral load at time of suspected CMV disease up to 12 months post-transplant in the intent-to-treat (ITT) population
 Percentage (no.) of patients
Peak CMV viral load
(copies/mL)
Valganciclovir
(n = 87)
Ganciclovir
(n = 42)
All CMV viral loads <40049.4 (43)33.3 (14)
400–500014.9 (13)14.3 (6)
5001–20 00020.7 (18)23.8 (10)
20 001–50 000 8.0 (7)21.4 (9)
50 001–100 000 3.4 (3) 7.1 (3)
>100 000 2.3 (2) 0 (0)
CMV viral load not done 1.1 (1) 0 (0)

Acute rejection and graft loss

The incidence of patients experiencing at least one episode of acute graft rejection was similar for both groups (Table 5). In general, the rate of acute graft rejection appeared to be lower with valganciclovir. The proportion of patients who experienced more than one episode of graft rejection during the 12-month follow-up was similar between the two groups (valganciclovir 11.3%, ganciclovir 11.2%). Only seven patients [valganciclovir, n = 5 (2.1%); ganciclovir, n = 2 (1.6%)] experienced acute graft rejection after CMV disease, and only five patients [valganciclovir, n = 3 (2 liver, 1 kidney); ganciclovir, n = 2 (2 kidney)] lost their graft during the 12-month study.

Table 5.  Summary of acute graft rejection by organ type up to 6 and 12 months post-transplant [intent-to-treat (ITT) population]
 Percentage (no.) of patients
 Valganciclovir (n = 239)Ganciclovir (n = 125)
Organ type6 months12 months6 months12 months
Total29.7% (71)32.6% (78)36.0% (45)36.0% (45)
Liver (n = 177)27.1% (32)28.8% (34)35.6% (21)35.6% (21)
Kidney (n = 120)21.0% (17)23.5% (19)23.1% (9)23.1% (9)
Heart (n = 56)57.1% (20)65.7% (23)71.4% (15)71.4% (15)
Kidney-pancreas (n = 11)40.0% (2)40.0% (2)0% (0)0% (0)

Safety

In general, the safety profile of valganciclovir was similar to that of oral ganciclovir. Table 6 summarizes the most frequent adverse events reported during study treatment plus 28 d. Most events occurred during the treatment phase and were mild or moderate in intensity (92% valganciclovir; 94% ganciclovir); the majority of adverse events were unrelated to treatment (92% valganciclovir; 93% ganciclovir). The proportion of patients experiencing events considered related to study drug (40.6% valganciclovir vs. 34.1% ganciclovir), and the proportions of patients withdrawing due to adverse events (4.9% valganciclovir vs. 5.6% ganciclovir), were similar for both treatment groups. Events that were both serious and treatment-related occurred in 7.0% of valganciclovir and 4.8% of ganciclovir recipients. Despite a trend towards higher investigator-reported adverse event rates of leucopenia (13.5% vs. 7.1%; p = 0.0667) and neutropenia (8.2% vs. 3.2%; p = 0.0631), and a higher proportion of patients – based on analysis of laboratory data – with absolute neutrophil count <1000 cells/μL (12.7% vs. 7.9%; p = 0.1661) in the valganciclovir group during and up to 28 d post-treatment, the proportion of patients discontinuing because of leucopenia or neutropenia was similar between groups (2.0% valganciclovir, 2.4% ganciclovir). Furthermore, more severe neutropenia (ANC < 500 cells/μL) was noted in only 4.9% and 3.2% of valganciclovir and ganciclovir patients, respectively, and there were no cases of neutropenia-associated sepsis. A slightly higher proportion of the ganciclovir group had a minimum platelet value <100 000/μL (25.6% vs. 18.9%; p = 0.1436) and a minimum hemoglobin level <8.0 g/dL (8.7% vs. 5.7%; p = 0.2771).

Table 6.  Summary of most frequent adverse events reported during study treatment plus 28 days (Safety population)
 Percentage (no.) of patients
 Valganciclovir
(n = 244)
Ganciclovir
(n = 126)
  1. See safety section for incidence of leucopenia, neutropenia and absolute neutrophil count.

Diarrhea29.9% (73)28.6% (36)
Tremor27.9% (68)25.4% (32)
Graft rejection24.2% (59)30.2% (38)
Headache21.7% (53)727.0% (34)
Nausea22.5% (55)23.0% (29)
Constipation20.1% (49)19.8% (25)
Lower limb edema20.5% (50)15.9% (20)
Insomnia20.1% (49)15.9% (20)
Back pain20.1% (49)15.1% (19)
Hypertension17.6% (43)15.1% (19)

Twenty-nine patients (7.8%) experienced at least one opportunistic infection during the treatment phase (7.4% valganciclovir vs. 8.7% ganciclovir). During treatment, mortality was low (2.0% valganciclovir vs. 1.6% ganciclovir) and considered unrelated to study drug. By 6 months, 11 patients had died: 9 patients (3.7%) on valganciclovir and 2 (1.6%) on ganciclovir; two deaths (valganciclovir, pneumonitis; ganciclovir, sepsis) were assumed to be related to CMV disease. By 12 months, 23 patients had died: valganciclovir n = 15 (6.1%; 12 liver, 2 heart, 1 kidney) vs. ganciclovir, n = 8 (6.3%; 7 liver, 1 kidney).

Pharmacokinetics

Systemic exposure [daily area under the concentration-time curve (AUC0–24  h)] to ganciclovir was 1.7-fold higher after valganciclovir than after ganciclovir administration (mean AUC0–24  h, 46.3 ± 15.2 vs. 28.0 ± 10.9). Systemic ganciclovir exposure after valganciclovir administration was consistent across the various allograft groups (mean AUC0–24 values were 46.0 ± 16.1 μg/h/mL, 40.2 ± 11.8 μg/h/mL and 48.2 ± 14.6 μg/h/mL, in liver, heart and kidney recipients, respectively), and covariate analyses showed no apparent effect of gender, age or race on the extent of ganciclovir exposure after valganciclovir administration. There was no clear association between systemic exposure to ganciclovir and the incidence of leucopenia and neutropenia.

Discussion

Valganciclovir, a valine ester pro-drug of ganciclovir, has significantly enhanced oral bioavailability compared with oral ganciclovir (the current standard of care for prevention of CMV disease) allowing for a convenient once-daily regimen (16). This double-blind, double-dummy, randomized study found a once-daily 900 mg regimen of valganciclovir to be as clinically effective and of comparable safety to a 1 g t.i.d. regimen of oral ganciclovir for the prevention of CMV disease in high-risk CMV D+/R- SOT recipients. Although there was a delay in the development of CMV disease in the valganciclovir arm, the proportion of patients developing CMV disease was comparable in the valganciclovir and ganciclovir arms, respectively, by both 6 months (Endpoint Committee-defined, 12.1% and 15.2%; Investigator-treated, 23.0% and 21.6%) and 12 months (Endpoint Committee-defined, 17.2% and 18.4%; Investigator-treated, 30.5% and 28.0%). By 12 months, a total of 47 patients (valganciclovir, n = 34, ganciclovir, n = 13) were treated for CMV disease by the investigator but were subsequently considered not have met the criteria for CMV disease by the Endpoint Committee. Most of these patients were considered not to have CMV disease as they did not experience fever, or did not record two episodes of fever >24 h apart. The vast majority of patients who developed CMV disease did so after the discontinuation of prophylaxis. This profile of late-onset CMV disease is now well recognized among transplant patients receiving antiviral prophylaxis (8).

Although overall incidences of CMV disease were comparable between the two arms of the study, differences in efficacy were observed across organ types; however, overall clinical outcomes in terms of graft and patient survival in our study are similar between groups and organ type and are superior to UNOS registry data (26).

No difference was observed with regards to the type of immunosuppressive regimen or specific use of anti-T cell antibodies between both study groups.

Valganciclovir was associated with enhanced antiviral activity compared with ganciclovir as indicated by the lower incidence of viremia during the treatment phase, the longer time to viremia, and the lower peak CMV loads (assessed in plasma samples). However, this increased degree of viral suppression with valganciclovir is presumably attributable to the higher ganciclovir exposures achieved with valganciclovir compared with ganciclovir (approximately 1.7-fold higher).

Ganciclovir exposure after 900 mg once-daily valganciclovir (mean AUC0–24  h, 46.3 μg/h/mL) was comparable with that reported previously for the same regimen of valganciclovir and for i.v. ganciclovir 5 mg/kg once daily in liver transplant recipients (16), and was consistent across the different allograft types.

As well as its direct clinical manifestations, CMV is associated with a number of indirect immunological effects, most notably allograft dysfunction and rejection in some settings (4). We questioned whether the improved bioavailability and antiviral efficacy of valganciclovir would translate into better control of these indirect effects. While not adequately powered to determine this, a trend towards reduced liver and heart rejection was observed with valganciclovir.

Previous studies suggest that CMV D+/R- patients are at high risk of developing ganciclovir resistant mutants during ganciclovir prophylaxis (19). As suboptimal suppression of viremia predisposes to development of resistance, the increased viral suppression with valganciclovir may reduce the frequency of emergence of ganciclovir-resistant virus. The emergence of resistance has been evaluated in the present trial and results are detailed elsewhere (27). Briefly, up to 1 year post-transplant, no ganciclovir-resistant mutations were associated with valganciclovir compared with a low incidence of such mutations with oral ganciclovir (1.9% (2/103) at end of ganciclovir prophylaxis (day 100) and 6.1% (2/33) for cases of suspected CMV disease (27). The incidence of ganciclovir resistance associated with ganciclovir prophylaxis in this study is much lower than those reported in recent single-center studies (19).

The enhanced antiviral suppression afforded by valganciclovir in this study did not appear to translate into a reduced overall and long-term incidence of CMV disease relative to ganciclovir. However, this study was not designed or powered to show superiority of valganciclovir compared with oral ganciclovir. To design and power such a study would have involved recruitment of ∼1000 patients which would have been difficult to achieve in a reasonable timeframe. It could be argued that a lack of difference in incidence of CMV disease between groups, despite enhanced potency and viral suppression with valganciclovir, might be the result of as yet undefined host factors unique to this subset of patients with late CMV disease (one avenue for investigation is whether these ‘refractory’ patients remain immunologically naïve to CMV at the time of antiviral discontinuation). Conditions associated with immune dysfunction and CMV reactivation, such as allograft rejection and treatment with high-dose methylprednisolone have been identified as important predisposing factors for late-onset CMV disease in high-risk SOT patients who received antiviral prophylaxis (8). This patient subset may therefore be unable to mount an appropriate immune response to control the emerging level of CMV replication after discontinuation of antiviral prophylaxis (28). However, the issue of whether antiviral prophylaxis alters CMV-specific immune-reconstitution is controversial. Indeed, while ganciclovir prophylaxis has been reported to delay the recovery of CMV-specific T-cell responses in bone marrow transplant recipients (29), ganciclovir treatment during primary viremia has been reported to assist in the rapid induction, maintenance and stabilization of CMV-specific cellular immune responses in SOT recipients (30). It is also important to note that ganciclovir-treated patients in the present study attained higher plasma ganciclovir exposures than would be expected from previous pharmacokinetic studies in SOT patients (mean AUC0–24  h, 28.0 vs. 20.7 μg/h/mL) (16) and therefore the difference in degree of exposure after valganciclovir and ganciclovir was not as great as has been reported previously (16).

Numerous studies have shown that once-daily regimens are associated with higher patient compliance than medications that require more frequent dosing (31,32), with a recent meta-analysis of 76 studies reporting a decrease in compliance from 79% with once-daily regimens to 65% with t.i.d. regimens (32). Improving compliance with medication is particularly important in the setting of antiviral therapy: as well as potentially reducing clinical and virological outcome, poor compliance predisposes to resistance development. While one would therefore intuitively expect that the simple once-daily valganciclovir regimen would confer improved patient compliance compared with a t.i.d. ganciclovir regimen with a high pill burden (12 capsules/day), unfortunately the double-dummy design of our trial precluded evaluation of the convenience aspect of the regimen and the impact of this on compliance and on other clinical and virological outcomes.

The 2:1 randomization schedule in this study facilitated collection of valganciclovir safety data. Overall, valganciclovir displayed a safety profile comparable to that of oral ganciclovir. There was a trend towards a higher incidence of leucopenia and neutropenia with valganciclovir but these events were well managed and the number of patients discontinuing for these reasons was similar between groups. There were no significant between-group differences in the incidence of deaths and other serious adverse events.

In conclusion, in this first clinical trial in transplant patients, valganciclovir was as clinically effective as oral ganciclovir with a comparable safety profile and the absence of ganciclovir resistance. Valganciclovir was also associated with superior exposure and consequently greater viral suppression and delay to viremia compared with oral ganciclovir. This convenient once-daily oral regimen of valganciclovir offers a clinically effective and well-tolerated option for CMV prevention in SOT patients.

Acknowledgments

This study was funded by Hoffmann-La Roche Ltd, Basel, Switzerland.

We would like to thank the following for their contributions to this study: independent Endpoint Committee (David Dunn, Department of Surgery, University of Minnesota, Minneapolis, MN, USA; Nina Singh, Infectious Disease Section, VA Medical Center, Pittsburgh, PA, USA; Thomas Gonwa, Mayo Clinic Transplant Center, Jackonsville, FL, USA).

Drug Safety Monitoring Board (Sarah Cheeseman, Department of Medicine, University of Massachusettes Medical School, Worcester, MA, USA; Carmen Cuffari, Department of Pediatrics, The John Hopkins Hospital, Baltimore, MD, USA; Micheal Eliasziw, Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; Andrew S Klein, Division of Transplant Surgery, The John Hopkins Hospital, Baltimore, MD, USA; Gerald R Winslow, Loma Linda University, Loma Linda, CA, USA).

Valganciclovir Study Group

There follows a complete list of the members of the Valganciclovir Solid Organ Transplant Study Group in Alphabetical order by country:

In Australia: Josie Eris, Royal Prince Alfred Hospital, Camperdown, NSW; Anne Keogh, St Vincent's Hospital, Darlinghurst, NSW; Tim Mathew, Queen Elizabeth Hospital, Woodville, SA; Geoff McCaughan, Royal Prince Alfred Hospital, Camperdown, NSW; Kathy Nicholls, Royal Melbourne Hospital, Parkville, VIC; Simone Strasser, Royal Prince Alfred Hospital, Camperdown, NSW.

In Canada: Atul Humar, Toronto General Hospital, Toronto, ON; Richard Lalonde, Montreal Chest Institute, Montreal, QC; Paul Marotta, London Health Sciences Center University Campus, London, ON; Jutta Preiksaitis, University of Alberta Hospital, Edmonton, AB; Eric Yoshida, Vancouver Hospital and Health Sciences Center, Vancouver, BC.

In France: Iradj Gandjbakch, Pitie-SalPetriere Hospital, Paris; Yvon Lebranchu, Bretonneau Hospital, Tours; Christophe Legendre, Saint-Louis Hospital, Paris; Faouzi Saliba, Hôpital Paul Brousse, Villejuif.

In Ireland: Oscar Traynor, St Vincents University Public Hospital, Dublin.

In Italy: Paolo Angeli, Azienda Ospedaliera Di Padova, Padova; Francesco Menichetti, Ospedale Cisanello, Pisa.

In New Zealand: Ed Gane, Auckland Hospital, Auckland.

In the United Kingdom: Ali Bakran, Royal Liverpool University Hospital, Liverpool; John Forsythe, Edinburgh Royal Infirmary, Edinburgh; Nigel Heaton, Kings College Hospital, London; Peter Lodge, St James Hospital, Leeds; Derek Manas, Freeman Hospital, Newcastle Upon Tyne; Peter Morris, Churchill Hospital, Oxford; Jayan Parameshwar, Papworth Hospital, Papworth Everard; Nizar Yonan, Wythenshawe Hospital, Manchester.

In the United States: Barbara Alexander, Duke University Medical Center, Durham, NC; Emily Blumberg, Hospital of the University of Pennsylvania, Philadelphia, PA; Daniel C Brennan, Barnes Jewish Hospital, St Louis, MO; Robert Brown, Columbia Presbyterian Medical Center, New York, NY; Ronald W Busuttil, UCLA School of Medicine, Los Angeles CA; Ken Chavin, Medical University South Carolina, Charleston, SC; David Conti, Albany Medical Center, Albany, NY; Angelo DeMattos, Oregon Health Sciences University, Portland, OR; Ed Dominguez, University of Nebraska Medical Center, Omaha, NE; Howard J Eisen, Temple University School of Medicine, Philadelphia, PA; Dan Fishbein, University of Washington, Seattle, WA; Thomas Fishbein, Mt Sinai Medical Center, New York, NY; Robert Fisher, Medical College of Virginia Hospital, Richmond, VA; Richard Freeman, New England Medical Center, Boston, MA; Chris Freise, University of California San Francisco, San Francisco, CA; Marquis Hart, UC San Diego Medical Center, San Diego, CA; Thomas Heffron, Emory University, Atlanta, GA; Ray E Hershberger, Oregon Health Sciences University, Portland, OR; Richard J Howard, University of Florida, Gainesville, FL; Sandra A Kemmerly, Alton Ochsner Medical Institution, New Orleans, LA; Richard Knight, Mt Sinai Medical Center, New York, NY; Bernard Kubak, UCLA School of Medicine, Los Angeles, CA; Shimon Kusne, University of Pittsburgh, Pittsburgh, PA; Steven Mawhorter, Cleveland Clinical Foundation, Cleveland, OH; Martin Mullen, Loyola University Medical Center, Maywood, IL; Carlos Paya, Mayo Clinic, Rochester, MN; Mark Pescovitz, Indiana University Medical Center, Indianapolis, IN; John Pirsch, University of Wisconsin Medical School, Madison, WI; Timothy L Pruett, University of Virginia Health Systems, Charlottesville, VA; Jeffrey Punch, University of Michigan Medical Center, Ann Arbor, MI; John Rabkin, Oregon Health Sciences University, Portland, OR; Robert Rubin, Massachusetts General Hospital, Boston, MA; John Scandling, Stanford University Medical Center, Palo Alto, CA; Michael Shapiro, Hackensack University Medical Center, Hackensack, NJ; Randi Silibovsky, Albert Einstein Medical Center, Philadelphia, PA; Kenneth Washburn, University of Texas Health Service Center, San Antonio, TX; Sam Weinstein, LifeLink Transplant Institute, Tampa, FL.

Ancillary