Retrospective review of the incidence of cytomegalovirus infection and disease after liver transplantation in pediatric patients: comparison of prophylactic oral ganciclovir and oral valganciclovir

Cytomegalovirus (CMV) is the most common viral infection after solid organ transplantation (SOT). Safe and effective prophylactic regimens that decrease its incidence after SOT are essential for long-term graft survival. Although valganciclovir is not Food and Drug Administration-approved for CMV prophylaxis in liver transplant recipients, postmarketing studies have shown valganciclovir to be as effective as ganciclovir in high-risk adult patients undergoing SOT. Currently, data are lacking for pediatric liver transplantation. The purpose of this study was to compare the efficacy and safety of valganciclovir and ganciclovir for CMV infection prophylaxis in pediatric liver transplant recipients. This was a retrospective study of 56 pediatric liver transplant recipients who were prescribed either oral ganciclovir (n = 37) or valganciclovir (n = 19). Patients were followed until 200 days after transplantation or death. The primary outcome measure compared the rates of early-onset CMV infection and CMV disease in the 2 medication groups. Secondary outcome measures identified patient-specific factors that contributed to CMV acquisition and the incidence of late-onset CMV infection or disease. The rates of adverse drug effects and discontinuation were also evaluated. Early-onset CMV disease was documented in 0% of valganciclovir patients and in 5.4% of ganciclovir patients (P = 0.54). There were no statistically significant differences in the secondary outcomes. An increased incidence of late-onset CMV disease was seen in the valganciclovir group versus the ganciclovir group (22.2% versus 8.1%, P = 0.23). No differences in adverse events were reported. In conclusion, no statistically significant differences were found in the incidence of CMV infection or disease between patients receiving oral valganciclovir and patients receiving oral ganciclovir.     

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

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.     

Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience

Recent data suggest valganciclovir (VGC) to be as effective as ganciclovir for cytomegalovirus (CMV) prophylaxis. The objective of this study was to analyze the effect of oral valganciclovir in renal transplant patients with symptomatic CMV infection. Twenty-one patients with symptomatic CMV infection received VGC in doses adjusted to renal function until resolution of CMV antigenemia. The patients were followed for a mean of 5.5 months. During therapy, CMV antigenemia dropped in all patients from pretreatment positive levels of 5.2 +/- 3.7 to negative values of 0.25 +/- 0.2 positive cells/10,000 PBMC (P<0.001). After cessation of therapy, none of patients developed relapse of CMV antigenemia/symptoms within the follow-up. VGC therapy was well tolerated in all patients and no major adverse effects occurred. This pilot trial showed VGC to be safe and highly effective in antiviral therapy after renal transplantation. However, subsequent multicenter clinical trials for treatment of CMV disease are necessary.     

Does valganciclovir hydrochloride (valcyte) provide effective prophylaxis against cytomegalovirus infection in liver transplant recipients?

INTRODUCTION: Cytomegalovirus (CMV) infection after solid organ transplantation is one of the most common viral infections, causing significant morbidity and mortality if not treated promptly. Ganciclovir has proven to be effective for the prophylaxis and treatment of CMV. However, oral absorption of ganciclovir is poor. Recently, oral administration of valganciclovir hydrochloride (Valcyte) has been observed to display 10-fold better absorption than oral ganciclovir. Valganciclovir has increasingly been used as prophylaxis against CMV after solid organ transplantation. The purpose of this study was to examine the efficacy of valganciclovir prophylaxis therapy after primary liver transplantation. PATIENTS AND METHODS: Between July 2001 and May 2003, 203 consecutive liver transplant recipients, including 129 men and 74 women of overall mean age 53 +/- 11 years, received valganciclovir (900 mg/d or 450 mg every other day depending on renal function) for 3 to 6 months after primary liver transplantation. All patients were followed up for a minimum of 6 months. Mean follow-up was 19 +/- 5.8 months. CMV DNA in peripheral blood was tested using polymerase chain reaction (PCR) amplification. Symptomatic CMV was stratified according to the CMV immunoglobulin (Ig)G status of the donor and recipient at the time of liver transplantation. Donors and recipients were classified preoperatively into groups according to the presence or absence of CMV as follows: group 1 (n = 73; donor CMV+, recipient CMV+); group 2 (n = 41; donor CMV-, recipient CMV+); group 3 (n = 54; donor CMV+, recipient CMV-; high-risk group); and group 4 (n = 35; donor CMV-, recipient CMV-). RESULTS: Twenty-nine patients (14.3%) developed symptomatic CMV disease at 169 +/- 117 days after liver transplantation: group 1, 16.4% versus group 2, 7.3% versus group 3, 25.9% versus group 4, 0%. Of these patients, 5 also had invasive CMV on liver biopsy, which was performed owing to abnormal liver functions. All 29 patients were treated with intravenous ganciclovir. One patient died owing to disseminated CMV, whereas the remaining 28 patients responded to treatment. Interestingly, 8 patients, including 1 who had invasive CMV hepatitis, developed symptomatic CMV within 90 days of liver transplantation even while on prophylactic valganciclovir. CONCLUSION: Valganciclovir failed to provide adequate prophylaxis following liver transplantation in our patients. The overall rate of CMV in seropositive donors and/or recipients was 17%, and in the high-risk group was 26%. Further prospective studies with measurement of ganciclovir concentrations are needed to elucidate the reasons for this unexpected failure.     

Efficacy of valganciclovir administered as preemptive therapy for cytomegalovirus disease in liver transplant recipients: impact on viral load and late-onset cytomegalovirus disease

BACKGROUND: The efficacy of valganciclovir used as preemptive therapy for cytomegalovirus (CMV) disease in liver transplant recipients is not known. METHODS: Between 1996 and 2004, surveillance testing using CMV antigenemia was performed at weeks 2, 4, 6, 8, 10, 12, and 16 posttransplant. A total of 28.8% (17/59) of the patients from 2001 to 2004 with antigenemia who received valganciclovir as preemptive therapy were compared with 26.2% (21/80) of the patients from 1996 to 2000 who received oral ganciclovir as preemptive therapy. RESULTS: The mean decline in the antigenemia level after initiation of valganciclovir and oral ganciclovir was 80.5% versus 50.7% at 1 week, 99.5% versus 89.4% at 2 weeks, and 100% versus 97.7% at 4 weeks, respectively. A higher proportion of patients who received valganciclovir (64.7%) belonged to the high-risk group (R-/D+) than patients who received oral ganciclovir (33.3%, P=0.10). Recurrent shedding was documented in 47.1% (8/17) of the patients in the valganciclovir group and 28.6% (6/21) of the patients in the oral ganciclovir group (P>0.20). Recurrent shedding correlated significantly with R-/D+ CMV serostatus and baseline CMV antigenemia level, regardless of the study group. No patient in either group developed CMV disease during or after the period of surveillance monitoring. The incidence of opportunistic infections and patient outcome did not differ for the valganciclovir group versus the oral ganciclovir group or patients without CMV infection (P>0.20). CONCLUSION: Antigenemia-directed valganciclovir as preemptive therapy seems to be effective for the prevention of CMV disease in liver transplant recipients, including high-risk patients.     

Prevention of Cytomegalovirus Disease in Renal Transplantation: Single-Center Experience

Cytomegalovirus (CMV) infection and CMV disease remain important issues in renal transplantation. Incidence depends on individual patient risk. There are different possible strategies for CMV prophylaxis. In our center CMV prevention includes prophylaxis with low-dose valganciclovir for all high-risk recipients; for the remaining patients, valganciclovir is only prescribed when there is evidence of CMV replication. All recipients are monitored for viral replication. We evaluated the results of this preventive strategy in all 135 patients who underwent transplantation between 2006 and 2007 in our center. Average follow-up time was 16 months (6-30 months). Fifty-one recipients (38%) received CMV prophylaxis. The median duration of prophylaxis was 84 days. In 37% of the recipients (50 patients) CMV antigenemia became positive, and were given therapeutic doses of valganciclovir. Of these patients, 32% were high-risk recipients undergoing prophylaxis. CMV infection rate was 40% in the group not receiving prophylaxis. No association was observed between CMV infection and prophylaxis duration. However, 50% of patients who suspended prophylaxis before completion of the first 3 months became infected. There were 3 cases of CMV disease (2.2%). Leukopenia was seen in 34% of patients receiving prophylaxis. Valganciclovir prophylaxis for high-risk patients seems to be effective and safe among subjects who complete the full duration of treatment. Despite CMV-positive antigenemia in 40% of patients not undergoing prophylaxis, pre-emptive therapy with valganciclovir was effective to prevent CMV disease, but close monitoring is essential for disease prevention.     

Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, controlled trial

BACKGROUND: The efficacy of pre-emptively administered oral ganciclovir in preventing cytomegalovirus (CMV) disease has not been documented in liver transplant recipients. We sought to compare the efficacy of pre-emptive oral ganciclovir with that of i.v. ganciclovir for the prevention of CMV disease after liver transplantation, and to determine whether withholding prophylaxis in the absence of CMV antigenemia, reliably identified patients in whom no prophylaxis was necessary. METHODS: Surveillance cultures for CMV pp65 antigenemia were performed in all patients at weeks 2, 4, 6, 8, 12, and 16. Patients with CMV antigenemia were randomized into two study groups. The experimental group received oral ganciclovir for 6 weeks (2 g t.i.d. for 2 weeks, then 1 g t.i.d. for 4 weeks), and the control group received i.v. ganciclovir (5 mg/kg q 12 hr) for 7 days. RESULTS: Of 72 consecutive liver transplant recipients studied, CMV antigenemia occurred in 31% (22 of 72). Twenty-two patients with asymptomatic antigenemia were randomized to two study groups. CMV disease (viral syndrome) occurred in 9% (1 of 11) of the patients in the i.v. ganciclovir group and in 0% (0 of 11) of the patients in the oral ganciclovir group. None of the study patients developed tissue invasive CMV disease. The median reduction in antigenemia level with oral ganciclovir was 55% at week 1, and 100% at week 2. Overall, 64% of the patients by week 1, 93% by week 2, and 100% by week 4 had antigenemia levels below the baseline after oral ganciclovir. Of 50 patients without CMV antigenemia, none developed CMV disease. CONCLUSIONS: Pre-emptive prophylaxis based on CMV antigenemia can effectively target the patients for CMV prophylaxis; 69% of the patients never received antiviral prophylaxis and did not develop CMV disease. Antiviral therapy instituted upon detection of antigenemia prevented tissue invasive CMV in both ganciclovir groups. Pre-emptively administered oral ganciclovir was effective as prophylaxis for CMV disease after liver transplantation.     

A Trial of Valganciclovir Prophylaxis for Cytomegalovirus Prevention in Lung Transplant Recipients

Cytomegalovirus (CMV) infection is common after lung transplantation. We performed a prospective trial of valganciclovir prophylaxis in lung recipients with outcomes compared to matched historical controls. The valganciclovir group (n = 40) (including D+/R- and R+ patients) was prospectively enrolled, and received oral valganciclovir 900 mg once daily for 12 weeks. Historical controls (n = 40) received 12 weeks of daily intravenous ganciclovir if D+/R- or 12 weeks of oral ganciclovir if R+. CMV viral load testing was done at two-week intervals until 6 months posttransplant. Baseline demographics and immunosuppression were comparable in the two groups. The incidence of CMV viremia was 16/40 (40.0%) in the valganciclovir arm versus 18/40 (45%) in the ganciclovir arm (p = NS). The incidence of symptomatic CMV disease was 8/40 (20%) versus 7/40 (17.5%), respectively (p = NS). In both groups viremia, while on prophylaxis, was uncommon (valganciclovir: 0/40 and ganciclovir: 2/40). Peak viral load and time to viremia were similar in the two arms. High rates of viremia and symptomatic disease occurred in the D+/R- patients after discontinuation of prophylaxis. Genotypic CMV sequence analysis demonstrated low rates of ganciclovir resistance in both groups. Valganciclovir prophylaxis had similar efficacy to either intravenous ganciclovir (D+/R- patients), or oral ganciclovir (R+ patients) in lung recipients.     

Cytomegalovirus Disease in High-Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis

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.     

Ganciclovir exposure under a 450 mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study

Manuel O, Pascual M, Perrottet N, Lamoth F, Venetz J‐P, Decosterd LA, Buclin T, Meylan PR. Ganciclovir exposure under a 450 mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study.
Clin Transplant 2010: 24: 794–800. © 2010 John Wiley & Sons A/S. Abstract: This prospective study aimed at determining the ganciclovir exposure observed under a daily dosage of 450 mg valganciclovir routinely applied to kidney transplant recipients with a GFR above 25 mL/min at risk for cytomegalovirus (CMV) disease. Ganciclovir levels at trough (C_trough) and at peak (C_{3 h}) were measured monthly. Ganciclovir exposure (area under the curve [AUC_0–24]) was estimated using Bayesian non‐linear mixed‐effect modeling (NONMEM). Thirty‐six patients received 450 mg of valganciclovir daily for three months. Median ganciclovir C_{3 h} was 3.9 mg/L (range: 1.3–7.1), and C_trough was 0.4 mg/L (range 0.1–2.7). Median AUC_0–24 of ganciclovir was 59.3 mg h/L (39.0–85.3) in patients with GFR_MDRD 26–39 mL/min, 35.8 mg h/L (24.9–55.8) in patients with GFR_MDRD 40–59 mL/min, and 29.6 mg h/L (22.0–43.2) in patients with GFR_MDRD ≥ 60 mL/min. No major differences in adverse events according to ganciclovir exposure were observed. CMV viremia was not detected during prophylaxis. After discontinuing prophylaxis, CMV viremia was seen in 8/36 patients (22%), and 4/36 patients (11%) developed CMV disease. Ganciclovir exposure after administration of valganciclovir 450 mg daily in recipients with GFR ≥60 mL/min was comparable to those previously reported with oral ganciclovir. A routine daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.     

Preemptive therapy with intravenous ganciclovir for the prevention of cytomegalovirus disease in lung transplant recipients

The most effective strategy for the prevention of cytomegalovirus (CMV) disease in lung transplantation has not been conclusively established. The aim of this study was to determine the efficacy of preemptive ganciclovir therapy for this purpose. Twenty-five consecutive adult patients positive for CMV before transplantation and surviving more than 30 days after the procedure were studied. Mean follow-up was 732.2 days (range, 210-1125). All patients received intravenous (IV) ganciclovir prophylaxis for the first 21 days and subsequently underwent frequent CMV antigenemia monitoring: weekly for the first 3 months, every 15 days between 3 and 6 months, and monthly thereafter. IV ganciclovir was given when antigenemia results were greater than 10 infected cells per 100,000 polymorphonuclears. The study group was compared with a historical group of 30 consecutive patients who had received IV ganciclovir prophylaxis and continued on oral ganciclovir up to day 120 posttransplantation. Eighteen of the 25 patients (72.0%) presented episodes of CMV infection. Six of the 25 patients (24.0%) had CMV disease, including 3 viral syndromes and 3 cases of pneumonitis. Four patients debuted with CMV disease, 1 of them with pneumonitis. CMV resistance to ganciclovir was observed in 2 patients. The incidence of infection was higher than in the historical group (72.0% vs 46.7%; P < .05), but there were no significant differences in the incidence of CMV disease (24.0% vs 40.0%; P = not significant [NS]). Mean time before onset of the first episode of disease was lower in the preemptive therapy group than in the comparison patients (82.8 days; range, 42-240 vs 175 days; range, 90-243; P < .05). In conclusion, preemptive therapy for CMV disease is as effective a prevention strategy as oral ganciclovir prophylaxis. However, the early appearance of CMV disease with preemptive therapy can make this approach inadvisable.     

Preemptive Therapy for Cytomegalovirus Disease in Allogeneic Stem Cell Transplant Recipients

Cytomegalovirus (CMV) infection causes high morbidity and mortality among allogeneic stem cell transplant recipients. Preemptive therapy with oral valganciclovir or intravenous ganciclovir has replaced universal prophylaxis. We prospectively studied 19 consecutive adult recipients of allogeneic peripheral blood stem cell transplants from May 2005 through February 2007 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. The antigenemia test was persistently negative in 8 patients (42%) and positive at least once in 11 (58%). Eight patients were treated with oral valganciclovir on an outpatient basis and they all became CMV negative after the first week of treatment. The other 3 patients received intravenous ganciclovir and were also CMV negative after the first week of treatment. No patient abandoned treatment, no severe secondary toxicity was noted, and there was no CMV-associated mortality.     

Impact of Prophylaxis vs Pre-emptive Approach for Cytomegalovirus Infection in Kidney Transplant Recipients

Cytomegalovirus (CMV) is the most common viral infection during the post-transplant period, and it is one of the major causes of morbidity and mortality in kidney transplantation. In this study, the incidence and impact of pre-emptive and prophylactic approaches and long-term effects on graft and patient survival of CMV infection were investigated. Among 493 adult kidney transplant recipients, pretransplant CMV IgG-negative patients and patients with a follow-up shorter than a month were excluded. The patients were divided into 2 groups: pre-emptive group (n = 187, regular screening and acyclovir 400 mg twice daily for 6 months), and prophylaxis group (n = 275, valganciclovir 450 mg/d for 3 months). The pre-emptive group was screened for CMV with either pp65 antigenemia or CMV DNA. There were 462 patients, and mean follow-up was 37.7 months. There were more CMV infections in the pre-emptive group than in the prophylaxis group (n = 56, 30.1% vs n = 12, 4.4%, respectively; P < .001). Late CMV infections were significantly more frequent in the prophylaxis group (10 of 12, 83.3%) than in the pre-emptive group (8 of 56, 14.3%, P < .001). In multivariate analysis, valganciclovir prophylaxis was associated with a lower CMV infection (relative risk [RR]: 0.18, 95% confidence interval [CI] 0.08 to 0.39, P < .001). Delayed graft function was the only independent risk factor for graft loss during the follow-up on multivariate Cox regression analysis (RR: 2.66, 95% GA 1.17 to 6.04, P = .02). Valganciclovir prophylaxis was more protective against CMV infection than the pre-emptive approach. Neither prophylaxis/pre-emptive approaches nor CMV infection had negative effect on graft and patient survival.     

Efficacy and Safety of Maribavir Dosed at 100 mg Orally Twice Daily for the Prevention of Cytomegalovirus Disease in Liver Transplant Recipients: A Randomized,Double‐Blind,Multicenter Controlled Trial

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double‐blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV‐seronegative liver transplant recipients with CMV‐seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)‐confirmed CMV disease within 6 months of transplantation. In a modified intent‐to‐treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: ?0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC‐confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non‐CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well‐tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.     

A Multicenter Study of Valganciclovir Prophylaxis up to Day 120 in CMV-Seropositive Lung Transplant Recipients

Seventy-six cytomegalovirus (CMV)-seropositive lung transplant recipients receiving valganciclovir (900 mg/day) for CMV prophylaxis were compared with a group of 87 patients receiving oral ganciclovir (3000 mg/day). Prophylaxis was administered to day 120 post-transplantation and follow-up was 1 year. In addition, a study was conducted on risk factors for CMV infection/disease. CMV disease incidence was 7.9% and 16.1% for valganciclovir and oral ganciclovir, respectively (p = 0.11). Patients receiving valganciclovir had fewer viral syndromes (2.6% vs. 11.5%, p < 0.05), a similar rate of tissue-invasive disease (5.2% vs. 4.6%, p = ns), longer time-to-onset of CMV infection/disease (197.5 vs. 155.2 days, p < 0.05), and a lower probability of infection/disease while on prophylaxis (1.3% vs. 12.6%, p < 0.01). Nonetheless, leukopenia incidence was higher with valganciclovir (15.8% vs. 2.3%, p < 0.01), as was the need for treatment withdrawal due to adverse effects (11.8% vs. 1.1%, p < 0.01). CMV infection was similar in both groups (32.9% vs. 34.5%). Induction therapy with basiliximab and glucocorticosteroid treatment were independent risk factors for developing CMV infection/disease. In conclusion, valganciclovir prophylaxis results in a low incidence of CMV disease in lung transplant recipients and appears more effective than oral ganciclovir. Despite the comparatively higher incidence of adverse events with valganciclovir, the drug can be considered safe for prophylaxis.     

Ganciclovir prophylaxis delays but does not prevent cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among renal transplant recipients. The purpose of this study was to examine the effect of routine prophylaxis with 12 weeks of oral ganciclovir on the incidence of CMV infection in a center that predominantly uses antibody induction together with tacrolimus/mycophenolate mofetil-based maintenance immunosuppressive therapy. The control group consisted of a historical patient cohort transplanted immediately prior to the use of oral ganciclovir prophylaxis. The use of tacrolimus (88% vs 77%, P=.02) and cytolytic therapy (81% vs 46%, P <.0001) was likewise greater among patients who received ganciclovir prophylaxis. CMV infection occurred in 20 (9%) patients in the ganciclovir era and 4 (3%) patients in the preganciclovir era (P=.003). The mean time to CMV infection was longer in patients who received ganciclovir prophylaxis than in patients in the preganciclovir era (23.4 +/- 10.9 weeks vs 9.8 +/- 5.6 weeks, P=.03). We conclude that 12 weeks of ganciclovir prophylaxis delays but does not prevent CMV infection from occurring in renal transplant recipients. These results suggest that with the use of 12 weeks of ganciclovir prophylaxis, vigilance for CMV infection is needed well beyond 24 weeks posttransplant.     

Primary CMV Infections Are Common in Kidney Transplant Recipients After 6 Months Valganciclovir Prophylaxis

Prolonging cytomegalovirus (CMV) prophylaxis in CMV seronegative recipients of a kidney from CMV seropositive donor (D+/R–) may reduce the incidence of late infections. We analyzed late‐onset primary CMV infections after 6 months valganciclovir prophylaxis. Data from all CMV D+/R– kidney transplant recipients between January 2004 and December 2008 at our center were analyzed. Patients with a functioning graft at 6 months after transplantation who received 6 months of valganciclovir prophylaxis 900 mg once daily were included (N = 127). CMV was diagnosed with quantitative PCR. Prophylaxis was completed in 119 patients. Prophylaxis was stopped at 3–5 months due to leukopenia or gastrointestinal side effects in eight patients. Late‐onset primary CMV infection developed in 47/127 (37%) patients median 244 days after transplantation (range 150–655) and median 67 days after the cessation of prophylaxis (range 1–475). Four infections were asymptomatic. In others, symptoms included fever (N = 28), gastrointestinal symptoms (nausea, vomiting, diarrhea) (N = 24), respiratory tract symptoms (N = 12), and hepatopathy (N = 6). Median peak viral load was 13500 copies/mL (range 400–2 831 000). Recurrent CMV infection developed in 9/47 (19%) patients. No significant risk factors for CMV infection were identified. Symptomatic primary CMV infections were commonly detected also after prolonged valganciclovir prophylaxis.     

Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation

BACKGROUND: With the development of sensitive tests to detect cytomegalovirus (CMV) viremia, preemptive approaches become a reasonable alternative to general CMV prophylaxis. We performed a randomized trial comparing pp65-antigenemia guided preemptive therapy using oral ganciclovir with symptom-triggered intravenous ganciclovir treatment. METHODS: Eighty-eight of 372 liver transplant recipients developed antigenemia early after orthotopic liver transplantation. Twenty-eight symptomatic patients with antigenemia were excluded from randomization and treated with intravenous ganciclovir. Sixty pp65-antigen-positive asymptomatic patients were randomized to receive either oral ganciclovir 3x1 g/day for 14 days (group 1) or no preemptive treatment (group 2). Patients that developed CMV disease were treated with intravenous ganciclovir 2x5 mg/kg body weight for 14 days. The high-risk (Donor+/Recipient-) patients were equally distributed in the two study groups. RESULTS: Three of 30 (10%) patients on oral ganciclovir developed mild to moderate CMV disease compared with 6/30 (20%) patients in the control group. In the Donor+/Recipient- patients, the incidence of CMV disease was 1/6 and 3/7. All disease episodes resolved after intravenous treatment. The 1- and 3-year patient and organ survival was the same in the study groups and in the patients with or without CMV infection. No deaths related to CMV occurred. CONCLUSIONS: The positive predictive value of pp65-antigenemia for the development of CMV disease was very low, and, in 28/88 patients (32%), antigenemia did not precede symptoms. Therefore, pp65-antigenemia is of limited value in deciding on the timing and need for ganciclovir therapy after liver transplantation.     

Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients

BACKGROUND: A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir following oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS: The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS: Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. CONCLUSIONS: The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.     

The risk of cytomegalovirus recurrence after kidney transplantation

Recurrent cytomegalovirus (CMV) infections commonly occur after kidney transplantation. We studied the impact of secondary prophylaxis and other factors on the risk of CMV recurrence. All kidney transplant recipients between 2004 and 2009 in our institution were analyzed (N = 254). Patients with CMV infection were included (N = 62). CMV infections were diagnosed with quantitative PCR. CMV D+/R- recipients received 6 months valganciclovir prophylaxis, after which DNAemia was monitored. After treatment, secondary prophylaxis with valganciclovir was given at the clinician's discretion for 2-26 weeks and CMV DNAemia was monitored. Altogether 43 reactivations and 19 primary infections occurred. Antiviral treatment with valganciclovir or ganciclovir was given to 45 patients; 34/62 (55%) patients received secondary prophylaxis for mean 62 days (range 14-180 days). CMV recurrence occurred in 14/43 (33%) seropositive patients and in 4/19 (21%) patients after primary infection. In logistic regression, delayed graft function (OR 3.4) and high viral load (>100 000 copies/ml) at initial diagnosis (OR 5.9) predicted recurrence. Use or length of secondary prophylaxis, CMV serostatus, level of immunosuppression, HLA mismatch, antiviral treatment, or time to clearance of viremia during treatment did not predict recurrence of CMV. CMV recurrences occur commonly despite secondary prophylaxis. High viral load at diagnosis predicted the risk of recurrent CMV infection.