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.     

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.     

Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.     

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.     

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.     

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.     

Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults     

Prophylactic Versus Preemptive Oral Valganciclovir for the Management of Cytomegalovirus Infection in Adult Renal Transplant Recipients

Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R-, D+/R+, D-/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n=49) or preemptive therapy (900 mg b.i.d. for 21 days, n=49) for CMV DNAemia (CMV DNA level>2000 copies/mL in >or=1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p=0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R- and 1 D+/R+) in the prophylactic group and one (D+/R-) in the preemptive group. Peak CMV levels were highest in the D+/R- patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.     

Clinical Utility of Cytomegalovirus Viral Load Testing for Predicting CMV Disease in D+/R- Solid Organ Transplant Recipients

Despite prophylaxis, cytomegalovirus (CMV) disease is common in donor seropositive (D+)/recipient seronegative (R-) transplant patients after cessation of prophylaxis. Early detection of CMV may allow for pre-emptive therapy to prevent active disease. The clinical utility of quantitative plasma viral load measurements for predicting CMV disease was determined in 364 D+/R- organ transplant patients receiving prophylaxis (100 d of valganciclovir or oral ganciclovir). Measurements were performed every 2 weeks until day 100 and at months 4, 4.5, 5, 6, 8 and 12 post-transplant. CMV disease occurred in 64 (17.6%) patients by 12 months. Using a positive cut-off value of >400 copies/mL, sensitivity was 38%, specificity 60%, positive predictive value 17%, and negative predictive value 82% for prediction of CMV disease. Therefore, routine monitoring would have predicted disease in only 24/64 (38%) patients. The test characteristics were not improved by changing the viral load cut-off point for defining a positive result. Similarly, single time point measures at the end of prophylaxis or month 4 had low sensitivity for disease prediction. Overall, regular CMV plasma viral load measurements were only of modest value in predicting CMV disease.     

Valacyclovir Prophylaxis Versus Preemptive Valganciclovir Therapy to Prevent Cytomegalovirus Disease After Renal Transplantation

Both preemptive therapy and universal prophylaxis are used to prevent cytomegalovirus (CMV) disease after transplantation. Randomized trials comparing both strategies are sparse. Renal transplant recipients at risk for CMV (D+/R−, D+/R+, D−/R+) were randomized to 3-month prophylaxis with valacyclovir (2 g q.i.d., n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia (≥2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. The 12-month incidence of CMV DNAemia was higher in the preemptive group (92% vs. 59%, p < 0.001) while the incidence of CMV disease was not different (6% vs. 9%, p = 0.567). The onset of CMV DNAemia was delayed in the valacyclovir group (37 ± 22 vs. 187 ± 110 days, p < 0.001). Significantly higher rate of biopsy-proven acute rejection during 12 months was observed in the preemptive group (36% vs. 15%, p = 0.034). The average CMV-associated costs per patient were $5525 and $2629 in preemptive therapy and valacyclovir, respectively (p < 0.001). However, assuming the cost of $60 per PCR test, there was no difference in overall costs. In conclusion, preemptive valganciclovir therapy and valacyclovir prophylaxis are equally effective in the prevention of CMV disease after renal transplantation.     

Long-Term Outcomes of CMV Disease Treatment with Valganciclovir Versus IV Ganciclovir in Solid Organ Transplant Recipients

Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3–11.3], p = 0.012; virological: OR 5.6 [2.5–12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.     

Following Universal Prophylaxis with Intravenous Ganciclovir and Cytomegalovirus Immune Globulin, Valganciclovir is Safe and Effective for Prevention of CMV Infection Following Lung Transplantation

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at-risk (donor positive/recipient negative [D+/R-] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV-IVIG) followed by valganciclovir (450 mg twice-daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high-dose oral acyclovir following i.v. GCV and CMV-IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100-179 days (64%) or < 100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV-IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at-risk lung transplant recipients. The required length of prophylaxis was at least 180 days.     

Clinical Utility of Cytomegalovirus (CMV) Serology Testing in High-risk CMV D+/R− Transplant Recipients

Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R- solid organ transplant (SOT) patients who receive antiviral prophylaxis. We assessed the clinical utility of CMV IgG and IgM serology testing for predicting late-onset CMV disease. We evaluated 352 D+/R- transplant recipients who participated in a trial comparing 100 days of ganciclovir versus valganciclovir prophylaxis. CMV serology was assessed on day 28, 56, 100, and 6 and 12 months post-transplant. IgG seroconversion occurred in 26.9% of patients by day 100, and in 63.4% and 75.3% by 6 and 12 months, respectively. IgM seroconversion occurred in 8.3%, 41.8% and 54.9% by day 100, month 6 and month 12, respectively. Seroconversion by day 100 (end of prophylaxis) was not predictive of subsequent CMV disease (CMV disease 13.3% if seropositive vs. 17.8% if seronegative; p = NS). However, at 6 months post-transplant, IgG serostatus was predictive of subsequent CMV disease between month 6 and 12 (CMV disease 1.3% if seropositive vs. 10.0% if seronegative; p = 0.002). In D+/R- patients, CMV serology testing is for the most part not clinically useful for predicting subsequent disease. However, seroconversion by 6 months may be useful for identifying patients at risk of late-onset CMV disease.     

Low-Dose Valganciclovir for Cytomegalovirus Prophylaxis in Heart Transplant Recipients

We retrospectively assessed our center's experience with a protocol of low-dose (450 mg once daily) valganciclovir administered for 3-6 months (median 5 months) in a cohort of of 55 cytomegalovirus (CMV) donor-positive (D+) and/or recipient-positive (R+) heart transplant recipients. Although no CMV disease occurred in patients while receiving low-dose valganciclovir, during the 12-month post-transplantation observation period of this study, 4 (22.2%) of the 18 D+/R− patients and 1 (2.7%) of the 37 R+ patients developed symptomatic CMV viremia. Leukopenia was frequent, including neutropenia [absolute neutrophil count (ANC), <1,000 cells/μL] that occurred in 21.8% and severe neutropenia (ANC <500 cells/μL) in 7.3%. Among CMV R+ heart transplant recipients, low-dose valganciclovir appeared to be an effective, less expensive strategy for CMV prophylaxis; however, caution may be necessary among D+/R− recipients.     

The Efficacy and Safety of 200 Days Valganciclovir Cytomegalovirus Prophylaxis in High‐Risk Kidney Transplant Recipients

Late‐onset cytomegalovirus (CMV) disease is a significant problem with a standard 3‐month prophylaxis regimen. This multicentre, double‐blind, randomized controlled trial compared the efficacy and safety of 200 days’ versus 100 days’ valganciclovir prophylaxis (900 mg once daily) in 326 high‐risk (D+/R–) kidney allograft recipients. Significantly fewer patients in the 200‐day group versus the 100‐day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200‐day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy‐proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild‐to‐moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days’ prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.     

Pharmacokinetics of Low and Maintenance Dose Valganciclovir in Kidney Transplant Recipients

Valganciclovir is commonly used for cytomegalovirus (CMV) prophylaxis in renal transplant patients. A fixed dose of 900 mg daily is typically recommended, however, there has never been a formal pharmacokinetic study comparing various doses in renal transplant patients. We therefore compared the pharmacokinetic characteristics of intravenous ganciclovir (IV GCV) and oral ganciclovir (GCV) with two different doses of valganciclovir (VGCV) in an open-label crossover study. Ten adult kidney recipients participated in a four-phase crossover treatment schedule of IV GCV (2.5 mg/kg every 12 h), VGCV (900 mg daily), VGCV (450 mg daily) and oral GCV (1000 mg Q8 H). IV GCV and oral VGCV 900 mg daily achieved similar values for AUC_0–24 (median 60.63 vs. 62.86 μg/h/mL). Oral VGCV 450 mg achieved comparable AUC_0–24 values as oral GCV 1000 mg Q8 H (median AUC_0–24 35.9 vs. 29.04 μg/h/mL). Oral VGCV 900 mg daily provided systemic GCV exposure similar to IV GCV and confirms PV 16 000 study results. Further, VGCV 450 mg daily provided comparable systemic exposure versus oral GCV. Due to its favorable pharmacokinetic profile, data herein suggest that VGCV can be used in the early post-kidney transplant period, and that 450 mg daily provides ample drug exposure for effective CMV prophylaxis in kidney transplant patients.     

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.     

Treatment of Active Cytomegalovirus Disease with Oral Ganciclovir in Renal Allograft Recipients: Monitoring Efficacy with Quantitative Cytomegalovirus Polymerase Chain Reaction

Treatment regimens of patients with active cytomegalovirus (CMV) disease require 2-3 weeks of intravenous ganciclovir (GCV) with/without CMV hyperimmune globulin. Oral GCV is effective as a prophylactic agent in prevention of CMV disease. Here we explored the utility of oral GCV as a treatment of active CMV disease. Fifteen renal allograft recipients (CMV donor+/recipient- [53%], CMV donor+/recipient+ [40%] or CMV donor-/recipient+ [7%]) developed active CMV disease. Cytomegalovirus polymerase chain reaction (CMV-PCR) tests were performed at the time of presentation and patients were treated with oral ganciclovir 1 g tid (adjusted for renal function). Patients were monitored for efficacy of treatment by assessment of clinical symptoms and CMV-PCR. Treatment was continued until the CMV-PCR copy number was negative and symptoms resolved. The mean CMV-PCR copy number at the time of diagnosis was 580 copies/microg DNA (nl: < 5 copies/microg DNA). After 5-7 days of treatment, the mean copy number was 65 copies/microg DNA. Fourteen of 15 patients responded well to oral ganciclovir, with complete resolution of clinical symptoms and eradication of CMV-PCR positivity. One patient did not respond to oral ganciclovir therapy due to probable noncompliance. Our data suggest that oral ganciclovir treatment, coupled with careful CMV-PCR monitoring, may be a reasonable alternative to long-term intravenous ganciclovir.     

Preemptive Strategy for Ganciclovir Administration Against Cytomegalovirus in Liver Transplantation Recipients

In utilizing a preemptive strategy to minimize the occurrence of symptomatic cytomegalovirus (CMV) infection following liver transplant, only patients with proven CMV activity by direct detection are treated. We applied the following preemptive strategy for CMV infection to 49 sequential liver transplant recipients between 1998 and 2001. Patients were monitored for CMV activity using CMV p65 antigen assay for the first 10 months of the study. Thereafter, we changed the detection method to a quantitative PCR for plasma CMV-DNA. All patients were monitored post transplant, weekly for the first 3 months and then monthly. Only patients with detected CMV activity were treated with ganciclovir. Patients were divided into four groups, based on donor (D) and recipient (R) CMV status. In seven out of 49 patients (14.3%) CMV activity was detected: four in group D+/R-, and three in group D-/R-. Five out of these seven patients had asymptomatic CMV infection. Symptomatic CMV infection developed only in two of these seven patients, to give total rate of 4.1% (2/49). All seven patients developed CMV IgG antibody. 'Transient' CMV replication detected by PCR in five patients in group D+/R+ was not defined as infection. No patients developed organ-invasive CMV disease. The cost of anti-CMV treatment using the preemptive strategy was $1000/patient/1st year. Using preemptive strategy, early detection of CMV infection was achieved, allowing timely treatment. The use of ganciclovir for CMV infection in only 4.3% of the patients should have a positive impact on minimizing the risk of ganciclovir-resistant virus, and should reduce the cost of CMV prevention strategies.