Valganciclovir Prophylaxis Research Articles

697 Extended Valganciclovir Prophylaxis (VGC px) Decreases CMV Disease in D+/R− Lung Transplant Recipients (LTR), but Is Limited by Late Onset Infections, Toxicity and Resistance

697 Extended Valganciclovir Prophylaxis (VGC px) Decreases CMV Disease in D+/R− Lung Transplant Recipients (LTR), but Is Limited by Late Onset Infections, Toxicity and Resistance

Importance of the cytomegalovirus seropositive recipient as a contributor to disease burden after solid organ transplantation

BackgroundThe incidence of cytomegalovirus (CMV) syndrome/disease after adult solid organ transplantation in the era effective antiviral therapy has not been fully assessed. ObjectiveTo determines the incidence of CMV syndrome/disease after solid organ transplantation in the UK. Study designA retrospective analysis of 1807 solid organ transplants from 12 UK solid organ transplant centres representing 32.7% of all transplant activity occurring in the UK between 1/04/2004 and 31/03/2006. Patients were categorised into those experiencing an episode of symptomatic CMV infection after transplant or those who remained free of symptoms. All patients were followed up for 2 years for the occurrence of CMV syndrome/disease. ResultsThe majority of the transplant centres used valganciclovir prophylaxis in the high risk D+R− patients (91.6%) whereas management of the lower risk D+R+ and D−R+ patients was more variable with deployment of both prophylactic and pre-emptive strategies in ∼50% of centres. CMV syndrome/disease occurred in 20.5% of the D+R− patients representing 55 cases whereas the incidence was only 8.1% and 9% in the D+R+ and D−R+ group, respectively (p<0.001 compared to the D+R− group), but representing a further 58 cases of CMV syndrome/disease. CMV viraemia in the D+R− group was associated with a high probability (65%) of CMV syndrome/disease in renal transplant recipients whereas this was less apparent in the intermediate risk groups. ConclusionsCMV syndrome/disease remains an important healthcare burden after solid organ transplantation with the intermediate risk groups contributing similar numbers of cases as the high risk group.

Cytomegalovirus disease and infection in lung transplant recipients in the setting of planned indefinite valganciclovir prophylaxis

The optimal method of both predicting and preventing cytomegalovirus (CMV) disease in lung transplant recipients remains unclear. In particular, the most appropriate duration of CMV prophylaxis post transplant is unresolved. We report herein our experience with a planned indefinite regimen of valganciclovir prophylaxis and monitoring of quantitative CMV load in bronchoalveolar lavage (BAL) fluid. We performed a single-center observational study with both prospective and retrospective components. The included patients (n = 128) received a planned regimen of indefinite valganciclovir prophylaxis post transplant, regardless of donor (D)/recipient (R) CMV serostatus. Real-time polymerase chain reaction assay for detection of CMV in BAL was prospectively performed over a 1-year period. Clinical data were reviewed retrospectively; median follow-up was 24.8 months (range 1-93 months). Sixty-five patients (50.6%) discontinued valganciclovir prophylaxis, either temporarily or permanently, with a primary cause of mild leukopenia. Six cases of CMV disease were identified (4.7%), with no significant difference between those who were on continuous prophylaxis or not (4.6% vs. 4.9%; P = non-significant [ns]). However, those who discontinued prophylaxis showed an increased incidence of laboratory-detected CMV infection (40.7% vs. 12.7%; P = 0.001). High-risk D+/R- patients did not demonstrate a significantly increased incidence of CMV disease (8.1% vs. 3.3% other serotypes; P = ns). Three patients (2.3%) developed valganciclovir-resistant CMV disease. Molecular detection of CMV in BAL fluid was significantly more sensitive than shell vial culture. However, BAL CMV viral load was not predictive of subsequent disease development. Extended valganciclovir prophylaxis for all lung transplant recipients led to a low incidence of CMV disease and resistance. In such low-incidence populations, routine quantitation of CMV in BAL did not confer significant clinical benefit over non-quantitative methods in prediction of CMV disease onset.

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial

Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis. Prophylaxis was 2 × 450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2 × 900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D-/R+]; 146 receiving prophylaxis and 150 preemptive therapy). Overall, CMV infection (asymptomatic CMV viral load ≥ 400 CMV DNA copies/mL proven by CMV-PCR) was significantly higher in recipients under preemptive therapy (38.7% vs. 11.0%, P<0.0001), with the highest incidence in D+/R+ preemptive patients (53.8% vs. 15.6%, P<0.0001). D+/R+ recipients with preemptive therapy also had the highest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003). Renal function assessed by creatinine clearance was similar for both groups. Graft loss occurred in 7 vs. 4 patients on preemptive versus prophylactic therapy (P>0.05). Tolerability was similar for both treatment groups. Oral valganciclovir prophylaxis significantly reduces CMV infection and disease, particularly for D+/R+ patients. Hence, our study supports routine prophylaxis for all D+/R+ recipients.

Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis

BackgroundThe IMPACT study was a randomized, double-blind study comparing 100 to 200 days of VGCV prophylaxis (900mg once daily) in D+/R− kidney transplant recipients. Although extending the duration of prophylaxis resulted in a significant reduction in confirmed cytomegalovirus (CMV) disease (100-day: 36.8% vs 200-day: 16.1%1), the consequence of extending the duration of prophylaxis on the development of viral resistance remains unknown. ObjectiveTo determine whether extending valganciclovir prophylaxis from 100 days to 200 days increased the incidence of ganciclovir resistance. Study designGenotypic analysis of CMV UL97 and UL54 was conducted on virus isolated from patients meeting the predefined resistance analysis criteria (RAC). ResultsA greater number of patients met the RAC in the 100 day prophylaxis arm (50/163; 31%) compared to the 200 day prophylaxis arm (22/155; 14%). Sequence data were successfully generated for all 200-day patients and 48/50 100-day patients. Three patients in each treatment arm (100 day: 3/163 (1.8%) vs 200 day: 3/155 (1.9%)) had a single known valganciclovir resistance mutation detected (100 day: UL97 gene: M460V, C592G twice; 200 day: UL97 gene: C603W, M460V and UL54 gene: P522S). Overall, a resistance mutation was more likely to be detected if the patient met the RAC during prophylaxis (5/12 (42%)) compared to post-prophylaxis (1/58 (2%)). All six patients with known ganciclovir resistance mutations cleared the virus; three cleared virus without treatment and three cleared virus following treatment. ConclusionsExtending valganciclovir prophylaxis from 100 days to 200 days did not significantly affect the incidence of ganciclovir resistance.

Profilaxis de la infección por citomegalovirus en el trasplante renal

Cytomegalovirus (CMV) infection remains a major problem in renal transplant recipients. CMV produces not only febrile syndromes and/or visceral disease but also contributes to the development of acute rejection and chronic graft failure. Valganciclovir prophylaxis has represented a major advance in controlling this infection, but late CMV infection after prophylaxis can occur, especially when universal prophylaxis is used. The use of valganciclovir prophylaxis for 200 days is more effective than prophylaxis for 100 days but does not completely prevent this problem. Prophylaxis based on the detection of CMV viremia (early prophylaxis or preemptive therapy) may prevent the development of delayed CMV disease, but has the disadvantage of requiring more intensive monitoring of viremia and does not prevent the development of viremia and its potential consequences in the long term. This article reviews current recommendations for prophylaxis of CMV disease in renal transplantation.

May the Indirect Effects of CIHHV-6 in Transplant Patients be Exerted Through the Reactivation of the Viral Replicative Machinery?

May the Indirect Effects of CIHHV-6 in Transplant Patients be Exerted Through the Reactivation of the Viral Replicative Machinery?

Valganciclovir Prophylaxis against Cytomegalovirus Impairs Lymphocyte Proliferation and Activation in Renal Transplant Recipients

Antiviral prophylaxis against cytomegalovirus has been associated with reduced risk of allograft rejection and improved allograft survival after renal transplantation. This phenomenon might not be fully explained by preventing the indirect effects of cytomegalovirus. The effect of antiviral agents on lymphocyte function in patients treated with modern immunosuppression has not been studied to date. Adult renal transplant recipients were assigned to 3-month prophylaxis with either valganciclovir (900 mg once daily; n=19) or valacyclovir (2 g four times daily; n=17) as part of an ongoing randomized trial. Subsets of lymphocytes, lymphocyte proliferation and/or cytokine production after in vitro mitogen stimulation were evaluated at the end of prophylaxis and 1 month after withdrawal of antiviral drugs. Lymphocyte proliferation was significantly decreased both after phytohemagglutinine (25% ±15% versus 32% ±18%; P=0.025) and concanavalin A stimulation (17% ±9% versus 25% ±16%; P=0.011) during valganciclovir, but not valacyclovir therapy. Moreover, a lower activated T-cell count (CD3(+)HLA-DR(+) cells) was noted in valganciclovir-treated patients (13% ±10% versus 17% ±12% of total CD3(+) T-cells; P=0.005). Valganciclovir suppresses lymphocyte proliferation and activation in patients after renal transplantation.

PIN56 Cost-Effectiveness Model to Evaluate 200-Day vs 100-Day Treatment with Valganciclovir Prophylaxis to Reduce Cytomegalovirus Disease in High-Risk (D+/R-) Kidney Transplant Recipient in Spain

PIN56 Cost-Effectiveness Model to Evaluate 200-Day vs 100-Day Treatment with Valganciclovir Prophylaxis to Reduce Cytomegalovirus Disease in High-Risk (D+/R-) Kidney Transplant Recipient in Spain

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.

Impact of Cytomegalovirus Disease in D+/R– Kidney Transplant Patients Receiving 6 Months Low-Dose Valganciclovir Prophylaxis

Late-onset cytomegalovirus (CMV) disease remains common in CMV serology naïve kidney transplant patients of CMV serology positive organs (D+/R-) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6-month low-dose valganciclovir (VGCV) prophylaxis, risk factors for late-onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R- kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow-up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively. The use of an induction agent with rabbit antithymocyte globulin and older donor age were factors associated with the risk of late-onset CMV disease (AHR 2.91, 95% CI 1.18-7.20, p = 0.021 and AHR 1.03, 95% CI 1.01-1.06, p = 0.016, respectively). Late-onset CMV disease was associated with increased risk for death-uncensored graft loss (AHR 2.95, 95% CI 1.15-7.61, p = 0.025). In conclusion, late-onset CMV disease continues to negatively impact kidney transplant outcome despite 6-month low-dose VGCV prophylaxis. Investigations focusing on novel preventive approaches should be emphasized.

Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients

Background Cytomegalovirus (CMV) remains the leading viral cause of disease following orthotopic liver transplantation (OLT) despite the availability of antiviral agents for prophylaxis and therapy. Objective Examine the viral factors that influence the outcome of CMV infection following valganciclovir prophylaxis or laboratory-guided preemptive therapy in OLT recipients. Study design The value of valganciclovir prophylaxis and laboratory-guided preemptive therapy for the prevention of CMV infection and disease was observed in 64 OLT recipients. Prophylaxis was given to all CMV seronegative recipients receiving a liver from a seropositive donor (D+R−; n = 15), and all other recipients were randomised to receive either prophylaxis ( n = 24) or laboratory-guided preemptive therapy ( n = 25). Recipients were monitored for CMV DNAemia, viral load, emergence of antiviral resistant strains and co-infections. Results CMV end-organ disease and antiviral resistant strains only occurred in D+R− recipients despite the use of prophylaxis in these patients. The D+R− recipients commencing prophylaxis immediately following transplantation had better outcomes compared to those for whom prophylaxis was delayed due to renal impairment. Prophylaxis reduced the incidence of CMV DNAemia, persistent infection, and high viral loads for CMV seropositive (D−R+and D+R+) recipients, but laboratory-guided preemptive therapy effectively controlled CMV infection and prevented disease in these OLT recipients. Conclusion Delaying the commencement of valganciclovir prophylaxis may be associated with worse outcomes for high-risk OLT recipients. Laboratory-guided pre-emptive therapy remains an alternative approach for seropositive recipients at lower risk of CMV disease.

Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: A single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial

The optimal approach to cytomegalovirus (CMV) prevention after lung transplantation is controversial. We recently completed a prospective, randomized, placebo-controlled study of CMV prevention in lung transplantation that demonstrated the short-term efficacy and safety of extending valganciclovir prophylaxis to 12 months vs 3 months of therapy. In the current analysis, we monitored a single-center subset of patients enrolled in the CMV prevention trial to determine if extended prophylaxis conferred a sustained long-term benefit and to assess its hematologic safety. The sub-analysis included 38 randomized patients from Duke University Medical Center. All patients underwent consistent serial serum CMV monitoring and surveillance bronchoscopies. CMV was defined by viremia (≥ 500 CMV DNA copies/ml) or pneumonitis. The safety assessment included a review of all complete blood counts obtained from transplant onward. During a mean follow-up of 3.9 years in each group, extended-course compared with short-course prophylaxis provided a sustained protective benefit with a lifetime CMV incidence of 12% vs 55%, respectively (hazard ratio, 0.13; 95% confidence interval, 0.03-0.61; p = 0.009), an effect that persisted after adjustment for clinical risk factors. Patients in each group underwent a comparable number of peripheral blood draws and bronchoscopies. Post-transplant white blood cell, neutrophil, and platelet counts were similar between each treatment group during the course of follow-up. Extending valganciclovir prophylaxis to 12 months provides a durable long-term CMV protective benefit compared with short-course therapy, without increasing adverse hematologic effects.

166 Indefinite Valganciclovir Prophylaxis among CMV D+/R- Lung Transplant Patients Is Limited by Breakthrough CMV Infections, Toxicity and Resistance

166 Indefinite Valganciclovir Prophylaxis among CMV D+/R- Lung Transplant Patients Is Limited by Breakthrough CMV Infections, Toxicity and Resistance

104 Reduced Lifetime Incidence of Cytomegalovirus with Extended Prophylaxis: Long-Term Follow Up from a Randomized Controlled Trial

The optimal approach to cytomegalovirus (CMV) prevention in lung transplant recipients is controversial. We recently completed the only randomized placebo-controlled study of CMV prevention in lung transplantation and demonstrated the short-term efficacy and safety of 12 months of valganciclovir prophylaxis (extended therapy) as compared to 3 months (short-course therapy). To examine whether extended therapy provides a long-term benefit we followed a single center subset of patients enrolled in the trial and assessed their lifetime incidence of CMV and hematological abnormalities.

Polyfunctional Cytomegalovirus-Specific Immunity in Lung Transplant Recipients Receiving Valganciclovir Prophylaxis

Cytomegalovirus (CMV) is a common opportunistic infection after lung transplant. Despite effective antiviral medications to treat CMV, invasive CMV disease contributes to lung allograft dysfunction and worse survival. Efforts to prevent CMV have led to the use of valganciclovir prophylaxis for increasingly longer periods after transplant. A pivotal concern with long-term antiviral prophylaxis is that it may prevent or delay the development of CMV-specific immunity and increase the subsequent risk of late onset disease. To address this issue, we conducted a pilot study to determine if CMV-specific immunity was detectable in lung transplant recipients at risk for CMV while on antiviral prophylaxis. Utilizing polychromatic flow cytometry panels, CMV-specific immunity was determined by peripheral blood CD4 and CD8 T cell expression of cytokines in response to the HLA restricted CMV peptides pp65 and IE-1. We determined CMV seropositive lung transplant recipients on valganciclovir for a median of 6 months from transplant have a detectable polyfunctional CMV-specific T cell response which is comparable to seropositive recipients not on antiviral medications and to healthy seropositive nontransplant controls. Thus, valganciclovir prophylaxis does not appear to impair the development of CMV-specific immunity in lung transplantation.

24 Weeks of Valganciclovir Prophylaxis in Children After Renal Transplantation: A 4-Year Experience

Cytomegalovirus (CMV) is the most common opportunistic infection after solid-organ transplant. Valganciclovir prophylaxis significantly reduces disease, but limited data are available on its use in children. Recently, an increase in delayed-onset CMV disease has been noted with some arguing that longer prophylaxis may decrease late-onset disease. Single-center, retrospective analysis of pediatric renal transplant patients receiving 24 weeks valganciclovir prophylaxis (15 mg/kg/day, maximum 900 mg/day) from January 2004 to December 2008, aiming to measure the incidence of CMV disease and toxicity of valganciclovir. We enrolled 111 patients, 60% males, 46% African Americans, and median age at transplant 14.5 years (range 1.4-20.4 years). Sixty-nine percent of donors and 44% of recipients were seropositive pretransplant. Median duration of valganciclovir use was 5.9 months (range 0.5-24 months). CMV viremia and disease occurred in 27% and 4.5%, respectively. All patients with disease presented after prophylaxis ended and all were D+/R-. Thymoglobulin use (P = 0.04) and positive donor CMV status (P = 0.02) were associated with a higher risk of CMV viremia. Twenty-four percent had hematologic toxicity directly associated with valganciclovir. Valganciclovir use in children was effective as prophylaxis against CMV disease; no children at our institution developed disease while on therapy. Our regimen of 24 weeks of prophylaxis was associated with a lower rate of late-onset disease than previous reports with 12-week regimens. Further controlled studies should be considered to compare longer versus shorter periods of prophylaxis and dose reductions and their impact on prevention of late-onset disease, resistance, cost, and toxicity.

Impact of a Preemptive Strategy After 3 Months of Valganciclovir Cytomegalovirus Prophylaxis in Kidney Transplant Recipients

We assessed the impact of a preemptive strategy after discontinuation of antiviral prophylaxis in the prevention of late-onset cytomegalovirus (CMV) disease in a cohort of kidney transplant recipients. Patients undergoing kidney transplantation at the University Hospital of Lausanne (CHUV) between November 2003 and November 2007 were included if they were donor or recipient (D/R) seropositive for CMV. All patients received 3 months of prophylaxis with valganciclovir, followed by monitoring of CMV DNAemia by polymerase chain reaction (PCR) every 15 days during 3 additional months. Valganciclovir was restarted if CMV PCR was more than or equal to 10,000 copies/mL. The primary endpoint of the study was the incidence of late-onset CMV disease. RESULTS.: Eighty-six kidney transplant recipients were included; 30 patients were D+/R- and 56 patients were R+ for CMV. At 6 months posttransplant, CMV DNAemia had occurred in 31 of 86 (36%) patients: 13 of 30 (43%) in the D+/R- group and 18 of 56 (32%) in the R+ group (P = 0.35). In the D+/R- group, among the 13 patients with CMV DNAemia, 7 (54%) patients developed late-onset CMV disease, simultaneously to the first positive viral load (n = 5) or after detection of low-grade viremia (n = 2). Only two patients received a preemptive treatment. In the R+ group, all positive PCR results were below the established cutoff. Thus, these 18 patients were not treated, and none of them developed late-onset CMV disease (R+ vs. D+/R-: P < 0.001). Within the limitations of a noncontrolled study, our data indicate that a preemptive strategy after 3 months of valganciclovir prophylaxis for CMV is not useful in R+ kidney transplant recipients. In D+/R- patients, this approach should be further evaluated.

A polymorphism linked to elevated levels of interferon-γ is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center

Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified. SNPs associated with varying levels of interferon (IFN)-γ (+874T/A), tumor necrosis factor-α (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV. Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-γ +874 T/T genotype (associated with high levels of IFN-γ production), CMV donor-positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-γ +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-γ +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-α, interleukin-10 or interleukin-6 SNPs and CMV infections. A genetic predisposition to elevated IFN-γ levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease.

Response to Questions Regarding the Design and Results of the IMPACT Trial

Response to Questions Regarding the Design and Results of the IMPACT Trial