Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients

BACKGROUND: Without effective antiviral prophylaxis, cytomegalovirus (CMV) disease is a common cause of morbidity and mortality after liver transplantation. In this randomized, controlled trial, we compared the efficacy and safety of oral ganciclovir with oral acyclovir after induction with intravenous (IV) ganciclovir for long-term prophylaxis of CMV disease in CMV-seropositive liver transplant recipients. METHODS: Patients were initially administered IV ganciclovir at a dose of 6 mg/kg per day from day 1 to day 14 after transplantation followed by either oral ganciclovir (1 g every 8 hr) or oral acyclovir (800 mg every 6 hr) from day 15 to day 100 after transplantation. RESULTS: CMV disease occurred in only 1 of 110 patients (0.9%) receiving ganciclovir compared with 8 of 109 patients (7.3%) receiving acyclovir within the first year after transplantation (P =0.019). There was one case of CMV colitis in the ganciclovir group, whereas four cases of CMV syndrome, three cases of CMV pneumonia, and one case of CMV hepatitis developed in the acyclovir group. The only death from CMV disease occurred in an acyclovir-treated patient with CMV pneumonia. Both oral ganciclovir and oral acyclovir were generally well tolerated. Reversible leukopenia (decline in white blood cell count to <3.0 x 10(9)/L) was more common with oral ganciclovir (38/110 patients, 35%) than with oral acyclovir (20/109 patients, 18%) (P =0.009). The emergence of ganciclovir-resistant strains of CMV was not found during the study. CONCLUSIONS: A prophylactic regimen of 2 weeks of IV ganciclovir followed by an additional 12 weeks of oral ganciclovir is superior to a similar regimen of IV ganciclovir followed by oral acyclovir and almost completely eliminates CMV disease after liver transplantation. This superior protection against CMV disease extends up to 1 year after transplantation and is not associated with ganciclovir resistance.     

A randomized prospective trial of oral versus intravenous ganciclovir for prophylaxis of cytomegalovirus infection and disease in high-risk kidney recipients

PURPOSE: This study was designed to compare the efficacy and safety of oral versus intravenous ganciclovir in high-risk kidney recipients. METHODS: Thirty-four, cytomegalovirus (CMV) seropositive recipients of kidneys from seropositive donors who had undergone antilymphocytic immunosuppressive therapy were assigned randomly to oral (1000 mg, three times a day, 12 weeks) versus intravenous (5 mg/kg, 2 weeks) ganciclovir prophylaxis. Follow-up was performed for 12 months. The patients were evaluated for clinical and laboratory outcomes regarding CMV serostatus, CMV disease, graft outcome, and ganciclovir side effects. RESULTS: Sixteen patients in the oral group and 14 in the intravenous group completed the study. CMV infection occurred in 6 (37.5%) and 5 (35.7%) cases in the oral and intravenous groups, respectively (P = NS). The mean interval between prophylaxis initiation and the first positive CMV Ag result was 3 +/- 2.19 months, with no significant difference between the two groups. Only two patients in the intravenous group experienced CMV diseases, which were not tissue-invasive. Acute rejection episodes were observed in nine out of 30 recipients, but it did not show any association with the prophylaxis regimen or CMV serostatus. The patients tolerated oral ganciclovir well; the compliance percent was 81.6%. No complication was reported. CONCLUSION: Oral and intravenous ganciclovir showed no significant difference to reduce the rate of CMV infection among high-risk kidney recipients. Oral ganciclovir was also effective and safe for the prevention of CMV disease. Moreover, it seems that CMV infection was not associated with acute rejection episodes.     

Long-term oral ganciclovir prophylaxis for prevention of cytomegalovirus infection and disease in cytomegalovirus high-risk renal transplant recipients

BACKGROUND: Although specific therapy is available with ganciclovir, cytomegalovirus (CMV) disease remains a major problem after renal transplantation especially in CMV seronegative recipients of organs of seropositive donors (D+R-). METHODS: In an open-labeled prospective controlled trial we evaluated the effect of long-term oral ganciclovir prophylaxis (3 g/day for 3 months posttransplantation) in a cohort of 31 CMV-high risk (D+R-) renal transplant recipients (GC) compared with a cohort of 28 high-risk patients with targeted CMV prophylaxis (CO) receiving i.v. ganciclovir during antirejection therapy. Primary end-points were CMV infection, diagnosed by pp65 antigenemia assay or serologic method, and CMV disease. Additionally severity of CMV disease quantified by a scoring system was evaluated. RESULTS: CMV prophylaxis significantly reduced the incidence of CMV infection (CO: 75%, GC: 45%; P<.05) and CMV disease (CO: 60%, GC: 29%; P<.05) without relevant side effects and without any clinical suspicion of ganciclovir resistance. Severity of CMV disease as quantified by a scoring system was reduced from 8.3+/-6.7 points in controls to 3.3+/-2.6 points in ganciclovir-treated patients (P<.05). Mortality did not differ significantly between the two groups (CO: n=3, GC: n=1; NS). However, there was one lethal CMV disease and a second death possibly attributable to CMV disease in the control group, whereas in ganciclovir-treated patients there was no CMV-associated fatal outcome. CONCLUSION: Long-term oral ganciclovir prophylaxis is effective and safe in CMV high-risk renal transplant recipients.     

Valganciclovir as preemptive therapy for cytomegalovirus in cytomegalovirus-seronegative liver transplant recipients of cytomegalovirus-seropositive donor allografts.

The efficacy of valganciclovir as preemptive therapy for the prevention of cytomegalovirus (CMV) disease and its impact on indirect sequelae of CMV were assessed in recipient-negative/donor-positive (R-/D+) liver transplant recipients. Of 187 consecutive liver transplant recipients at our institution since July 2001, 36 (19.2%) belonged to the R-/D+ group. Surveillance tests for CMV were performed on all patients at weeks 2, 4, 6, 8, 10,12, and 16. In all, 27 patients with asymptomatic viremia received preemptive therapy with valganciclovir. At a total follow-up of 62.8 patient years (median: 19 months, range: 3 months to 5.6 years), no episodes of CMV disease were documented in these patients. The incidence of rejection, retransplantation, and bacterial or fungal infections and the probability of survival did not differ for R-/D+ patients and all non-R-/D+ patients treated preemptively with valganciclovir (P > 0.20 for all variables). Thus, preemptive therapy with valganciclovir in R-/D+ patients was not associated with CMV disease during the period of surveillance monitoring or at anytime thereafter (late-onset CMV disease). The indirect outcomes with the use of valganciclovir in R-/D+ patients were comparable to the outcomes of other subgroups of liver transplant recipients receiving preemptive therapy.     

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.     

Randomized controlled trial of oral itraconazole solution versus intravenous/oral fluconazole for prevention of fungal infections in liver transplant recipients

BACKGROUND: Liver transplant recipients at high risk for serious fungal infections frequently receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole, safety with amphotericin B, and the cost of lipid formulations of amphotericin, alternative prophylactic regimens are needed. In this randomized, controlled trial, we compared the efficacy and safety of oral itraconazole solution with intravenous/oral fluconazole for prevention of fungal infections. METHODS: Adult liver transplant recipients were randomized to receive either oral itraconazole solution (200 mg every 12 hr) or intravenous/oral fluconazole (400 mg every 24 hr). Each study drug was started immediately before transplant surgery and continued for 10 weeks after transplantation. Patients were evaluated for fungal colonization, proven invasive or superficial fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization decreased from baseline to week 8 after transplantation in both the itraconazole patients (67% to 25%, P<0.001) and the fluconazole patients (77% to 30%, P<0.001). Proven fungal infection developed in 9 (9%) of 97 itraconazole patients and in 4 (4%) of 91 fluconazole patients (P =0.25). The number of proven invasive fungal infections (seven with itraconazole [7%], three with fluconazole [3%]) and proven superficial fungal infections (two with itraconazole [2%], one with fluconazole [1%]) were also similar in both groups of patients. Organisms causing infection were (four patients), (three patients), and species (two patients) in the itraconazole group and (two patients), (one patient), and species (one patient) in the fluconazole group. Mortality from fungal infection was very low and occurred in only 1 (0.5%) of 188 patients. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea) with itraconazole, both itraconazole and fluconazole were well tolerated and not associated with any hepatotoxicity. Mean trough plasma concentrations of itraconazole were greater than 250 ng/mL throughout the study and were not affected by H -receptor antagonists or antacids. CONCLUSION: Oral itraconazole solution has adequate bioavailability in liver transplant recipients for effective antifungal prophylaxis. Similar to fluconazole, prophylactic oral itraconazole decreases fungal colonization and is associated with a low incidence of serious or fatal fungal infections. Except for gastrointestinal side effects, oral itraconazole solution is well tolerated and has no significant hepatotoxicity.     

Prophylaxis versus preemptive therapy for cytomegalovirus disease in high-risk liver transplant recipients

Cytomegalovirus (CMV) infection is an opportunistic infection frequently found after solid organ transplantation, and it contributes significantly to mortality and morbidity. CMV-seronegative recipients of grafts from CMV-seropositive donors have the highest risk of CMV disease. The most appropriate strategy for preventing CMV disease in this population is a matter of active debate. In this study, we compared prophylaxis and preemptive therapy for the prevention of CMV disease in donor-seropositive/recipient-seronegative (D(+) /R(-) ) liver recipients. To this end, we selected a retrospective cohort of liver recipients (1992-2009) for analysis. D(+) /R(-) patients were identified from the liver transplant program database. Eighty of 878 consecutive liver recipients (9%) were D(+) /R(-) . Six of these patients died within 30 days of transplantation and were excluded. Thirty-five of the remaining D(+) /R(-) patients (47%) received prophylaxis, and 39 patients (53%) followed a preemptive strategy based on CMV antigenemia surveillance. Fifty-four (73%) were men, the median age was 49 years (range = 15-68 years), and the mean follow-up was 68 months (range = 8-214 months). The baseline characteristics and the initial immunosuppressive regimens were similar for the 2 groups. Ganciclovir or valganciclovir was the antiviral drug used initially in both strategy groups. CMV disease occurred more frequently among D(+) /R(-) liver recipients receiving preemptive therapy (33.3% versus 8.6% for the prophylaxis group, P = 0.01), whereas late-onset CMV disease was found only in patients receiving prophylaxis (5.7% versus 0% for the preemptive therapy group, P = 0.22). No significant differences in acute allograft rejection, other opportunistic infections, or case fatality rates were observed. According to our data, prophylaxis was more effective than preemptive therapy in preventing CMV disease in high-risk liver transplant recipients. Liver Transpl, 2012. ? 2012 AASLD.     

A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

Oral ganciclovir and valacyclovir reduce the incidence of cytomegalovirus (CMV) disease after renal transplantation (RTx). Our study was designed to compare the efficacy, costs, and safety of oral ganciclovir and valacyclovir in the prophylaxis of CMV disease over the first 6 months after RTx. A total of 38 patients was randomized to 3-month treatment with either oral ganciclovir (1 g t.i.d., n=14, GAN group) or oral valacyclovir (2 g q.i.d., n=12, VAL group). A third group (C, n=12) received no prophylaxis. The patients were monitored by CMV-nested PCR in whole blood. No differences were found between the groups in their demographic characteristics, immunosuppressive protocols, or donor and recipient CMV serology. Thirty-six out of 38 (94.7%) recipients were CMV-seropositive. Over the 6-month post-RTx period, there were 13 episodes of CMV disease in eight (66.7%) patients of the C group compared with none in the GAN and VAL groups ( P=0.0005, GAN vs C; P=0.001, VAL vs C). The incidence of CMV viremia was 30.8%, 50.0%, and 91.7% in the GAN, VAL, and C groups, respectively ( P=0.004, GAN vs C; P=0.07, VAL vs C; P=NS, GAN vs VAL). Treatment failure (death, graft loss, CMV disease, or withdrawal from study) occurred in 14.3%, 0% and 66.7% in the GAN, VAL, and C groups, respectively ( P=0.014, GAN vs C; P=0.001, VAL vs C; P=NS, GAN vs VAL). The average CMV-associated costs per patient (in 2001 euros) were 2,449+/-1,178, 2,485+/-581, and 4,259+/-4,616 in the GAN, VAL, and C groups, respectively. Ganciclovir and valacyclovir were well tolerated, with ganciclovir having had to be withdrawn shortly in one patient only because of thrombocytopenia. In conclusion, oral ganciclovir and valacyclovir are equally safe and effective in the prophylaxis of CMV disease after RTx. Both are cost-effective and help reduce CMV-associated costs by some 40% compared with patients without prophylaxis.     

Prospective comparison of valacyclovir and oral ganciclovir for prevention of cytomegalovirus disease in high-risk renal transplant recipients

AIMS: To compare the efficacy, costs and safety of oral ganciclovir and valacyclovir in the prophylaxis of cytomegalovirus (CMV) disease in renal transplant (RTx) recipients at high risk of CMV disease. METHODS: A total of 83 patients were prospectively randomized to 3-month treatment with either oral ganciclovir (3 g/day) or oral valacyclovir (8 g/day). A 3rd group received no prophylaxis. Forty-nine patients were considered to be at high risk of CMV disease due to D+R- serologic status, OKT3/ATG treatment and/or acute rejection within 12 months after RTx. Twenty-three high-risk patients were treated with ganciclovir (GAN group), 17 patients with valacyclovir (VAL group), and 9 patients received no prophylaxis (C group). RESULTS: No significant differences were found among the groups in their demographic characteristics, immunosuppressive protocols, D/R CMV serology, or CMV risk factors. The 12-month incidence of CMV disease was 89% in the C group compared with 9% in the GAN group and 6% in the VAL group (p < 0.001, GAN or VAL vs. C; p = 0.713, GAN vs. VAL). Treatment failure (death, graft loss, CMV disease or withdrawal from study) occurred in 17, 6, and 89% in the GAN, VAL, and C groups, respectively (p < 0.001, GAN or VAL vs. C; p = 0.285, GAN vs. VAL). The average CMV-associated costs per patient were EUR 3,161, 3,757, and 7,247 in the GAN, VAL, and C groups, respectively (p = 0.027). CONCLUSION: Valacyclovir and oral ganciclovir are equally effective in the prophylaxis of CMV disease in high-risk RTx patients. Both regimens are cost-effective and help reduce CMV-associated costs by nearly 50% compared with patients without prophylaxis.     

Comparison of combined prophylaxis of cytomegalovirus hyperimmune globulin plus ganciclovir versus cytomegalovirus hyperimmune globulin alone in high-risk heart transplant recipients

BACKGROUND: Seronegative heart transplant recipients who receive an allograft from seropositive donors have a higher risk of developing cytomegalovirus (CMV) disease and cardiac allograft vasculopathy (CAV) and dysfunction. Neither CMV-specific hyperimmune globulin nor ganciclovir as sole CMV prophylaxis is sufficient to prevent CMV disease in high-risk patients. We retrospectively evaluated the efficacy of CMV-hyperimmune globulin with and without ganciclovir in 207 D+/R- heart transplant recipients. METHODS: The study population was divided into two groups: Group A was composed of 96 patients who received CMV hyperimmune globulin as sole CMV prophylaxis, and group B was composed of 111 patients who received combined CMV prophylaxis. All recipients were subjected to quadruple cytolytic immunosuppression. Primary and secondary end points included prevention of CMV-associated death, CMV disease and productive infection, CAV, and overall infection. RESULTS: There was no difference in overall survival between the two groups. Four patients in the group A died of CMV sepsis, whereas no CMV-associated death was observed in group B (P =0.0326). The actuarial incidence of CMV disease was significantly lower in patients who received double CMV prophylaxis (32.29 vs. 11.71, P =0.0003). Although no difference was observed with regard to productive CMV infection (53.12 vs. 65.77, P =not significant), CAV and overall infection rates were significantly higher in the first group (7.29 vs. 0.9, P =0.0157 and 70.83 vs. 62.16, P =0.03, respectively). CONCLUSIONS: Double CMV prophylaxis consisting of CMV hyperimmune globulin and ganciclovir is able to abolish CMV death and prevent CMV disease in high-risk heart transplant recipients. Therefore, the use of a combination regimen is recommended for seronegative recipients with seropositive donors.     

Oral valgancyclovir versus intravenous gancyclovir for cytomegalovirus prophylaxis in kidney transplant recipients

BACKGROUND: Prophylaxis against cytomegalovirus (CMV) is a regular practice in organ transplantation. Oral valgancyclovir appears to be an interesting alternative to the usual intravenous form. PATIENTS AND METHODS: We prospectively compared the response of intravenous gancyclovir for 2 weeks (GAN; n=41) to oral valgancyclovir for 2 weeks (VAL2w; n=23) or 3 months (VAL3m; n=46) in kidney transplant recipients receiving induction immunosuppression. CMV antigenemia assay and/or polymerase chain reaction (PCR) were used for viral detection. Patients were followed for a minimum of 6 months posttransplantation. SPSS software was used for statistical analysis using a cutoff of significance as P<.05. RESULTS: There was no statistical difference in the demographic features among the study groups. However, human leukocyte antigen (HLA) match was better in the VAL3m group and the patients of this group received less ATG induction immunosuppression (41.3%) compared with the GAN group (100%). The incidence of acute rejection was not different among the study groups. There was a higher incidence of fever with positive CMV tests in the VAL2w group (P=.035) compared with the other groups, while leukopenia with a negative CMV test was significantly higher in the VAL3m group (P=.04). The incidence of CMV disease was higher in the VAL2w group (30.4%) compared with the GAN group (14.6%) or the VAL3m group (8.7%). Renal function was significantly worse in the VAL2w group at 3 and 6 months (P=.011 and .02, respectively). CONCLUSIONS: Three months oral valgancyclovir prophylaxis for CMV was a more effective regimen compared with intravenous gancyclovir for 2 weeks. Shorter courses were associated with a higher incidence of CMV infection and poorer graft function. Leukopenia observed in patients receiving valgancyclovir may be a drug-related side effect.     

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.     

Dosing of intravenous ganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplant recipients

BACKGROUND: The optimal regimen for the prevention and treatment of cytomegalovirus (CMV) disease in solid organ transplant recipients remains to be defined, particularly for patients with abnormal or changing renal function. METHODS: A prospective trial was conducted in patients receiving i.v. ganciclovir using a standardized dosing nomogram that corrects for renal function. Steady state peak (P) and trough (T) serum levels were determined by high-performance liquid chromatography and correlated with therapeutic outcomes and toxicities attributable to ganciclovir. RESULTS: Over the study period, 44 individuals received ganciclovir prophylaxis (5 mg(kg/day) and 25 patients were treated (5 mg/kd q12 hr) for symptomatic CMV disease. Ganciclovir levels (microg/ml+/-SD) achieved in prophylaxis were P: 7.98+/-3.34, T: 3.03+/-2.63; and in treatment were P: 9.00+/-3.72, T: 2.65+/-1.82. Despite corrections for renal dysfunction, undialyzed patients with serum creatinine >3.0 mg/dl had trough levels in excess of the population mean (T: range 3-8 microg/ml). Failure of prophylaxis (disease) or therapy (relapse) occurred in 14 patients; 8 of these were at risk for primary infection (donor CMV seropositive, recipient seronegative, P<0.01). Patients at greatest risk for relapse after treatment of CMV disease were liver transplant recipients, patients with ganciclovir-resistant viral isolates, and renal patients with six antigen MHC donor-recipient mismatches. CONCLUSIONS: This trial demonstrates the efficacy of a nomogram for ganciclovir dosing during renal dysfunction; reduced doses can be used for prophylaxis for undialyzed patients with renal dysfunction (1.25 mg/kg/day for Cr > or =3.0, 1.25 mg/kg QOD for Cr > or =5.0). Some groups of transplant recipients may require more intensive anti-CMV regimens.     

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis

BACKGROUND: The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. METHODS: The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. RESULTS: CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. CONCLUSIONS: Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.     

Delay of CMV infection in high-risk CMV mismatch lung transplant recipients due to prophylaxis with oral ganciclovir

Cytomegalovirus (CMV) is a common opportunistic infection in lung transplant recipients. Despite the use of early post-operative intravenous ganciclovir, most high-risk patients develop CMV infection. We conducted this retrospective study to determine the efficacy of extended CMV prophylaxis with oral ganciclovir in high-risk, donor-positive-recipient-negative, lung recipients. All patients initially received 3 months of intravenous ganciclovir and CMV hyperimmune globulin. Clinical outcomes in all CMV mismatch patients undergoing lung transplant surviving at least 3 months were included (n = 42). Since 1998, 14 patients received no oral ganciclovir prophylaxis (group 1) and 28 patients received indefinite oral ganciclovir after completion of intravenous therapy (group 2). In those patients receiving oral ganciclovir, the prevalence of post-transplant CMV infection was significantly reduced over the first 180 d post-transplant (50% in group 1 vs. 4% in group 2; p < 0.001). Although some CMV events were observed with additional follow-up in group 2, there remained a significantly greater freedom from CMV infection by Kaplan-Meier analysis in group 2 as compared with group 1, with over 30 months follow-up time in each group (log-rank, p = 0.02). A moderate rate of drug discontinuation was observed in group 2, and no severe drug-related events occurred. In high-risk lung transplant recipients, CMV prophylaxis with intravenous ganciclovir, followed by indefinite oral ganciclovir, significantly delays and reduces post-transplant CMV infections. A larger prospective randomized study is needed to confirm the benefits of oral ganciclovir on CMV prevention.     

Outcome of low-dose ganciclovir for cytomegalovirus disease prophylaxis in renal-transplant recipients

To assess the outcome of low-dose-ganciclovir prophylaxis (500 mg twice a day for 3 months) in renal-transplant recipients, a retrospective analysis of 185 patients transplanted between 1998 and 2001 was performed. There were 29 (15.6%) patients who belonged to the highest risk group, donor cytomegalovirus (CMV) positive, recipient negative (D + R-), and 37 (20%) patients in the lowest risk group, D-R-. Induction immunosuppression consisted of polyclonal antibody or OKT3 (n = 62, 33.5%), interleukin-2 receptor antibody (n = 61, 33%), and no induction (n = 62, 33.5%). CMV disease occurred in 13 (7%) patients. Highest incidence was in D + R- group (17.2%), with no cases in D-R- group (P = 0.03). Tissue-invasive CMV occurred in 4 of these 13 patients. In patients developing CMV disease, there was no evidence of ganciclovir resistance and no mortality over a mean follow-up of 42 months. Low-dose ganciclovir was found to be as effective in decreasing the incidence of clinical CMV disease as high-dose ganciclovir (1 gm three times a day for 3-6 months) in previous studies.     

Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients

BACKGROUND: Cytomegalovirus (CMV) D+/R- solid-organ transplant (SOT) recipients carry increased risk of developing CMV disease; however, other risk factors in these patients have not been delineated. METHODS: We examined 20 demographic and clinical variables for their association with the development of CMV disease, as defined by an independent endpoint committee (IEC) and also by the investigator (investigator treated [IT]), or CMV viremia within 12 months of transplant in D+/R- transplant recipients who received prophylaxis with valganciclovir or oral ganciclovir for 100 days. RESULTS: Recipients with low creatinine clearance (Ccr,<40 mL/min) at screening had a significantly increased hazard of developing IEC-defined CMV disease (hazards ratio [HR]=4.28, confidence interval [CI] 1.69, 10.83). Females were twice as likely (HR=2.19, CI .21, 3.99) to develop IEC-defined CMV disease than males. These variables were associated with an increased risk of IEC-defined CMV disease in time-dependent models. Recipients with blood group A were also more likely to develop IEC-defined CMV disease than those with group O (HR=2.36 CI 1.24, 4.51) in the logistic regression model only. Prophylactic drug, organ type, recipient age, rejection episodes, and maintenance immunosuppression regimen were not associated with IEC-defined CMV disease. Female sex was the only variable associated with the development of CMV viremia (odds ratio [OR]=1.65; CI 1.03, 2.65) and IT CMV disease (OR=1.78; CI 1.08, 2.93). CONCLUSIONS: Low Ccr at screening and blood type A are risk factors for IEC-defined CMV disease, and female sex was a risk factor for IEC- and IT-defined CMV disease and viremia in high-risk SOT recipients. These variables should perhaps be considered when optimizing treatment.