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.     

Prophylaxis of CMV disease by ganciclovir (DHPG) in seronegative recipients of renal allograft from seropositive donors

In an open-label randomized study of prophylactic treatment by ganciclovir, 23 seronegative recipients of kidney allograft from seropositive donors were randomized to receive from day 14 to day 28 after transplantation either no treatment (n = 11) or ganciclovir, 5 mg/kg twice daily (n = 12). Both groups were similar in age, immunosuppressive therapy, number of acute rejections and in steroid bolus. Seroconversion occurred in ten patients of the control group (91%) and in ten of the ganciclovir group (84%). CMV disease occurred in ten patients of the control group (91%) and in eight patients of the ganciclovir group (66%), three of whom had asymptomatic viraemia. The delay between transplantation and onset of CMV disease was significantly increased by ganciclovir prophylaxis (78.5 ± 7.7 vs 46.5 ± 7.5 days, P < 0.05). We conclude that in renal transplant recipients at risk of CMV disease, ganciclovir prophylaxis delays the onset of the disease and seems to decrease its incidence and its severity.     

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.     

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.     

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 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.     

Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients

Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups. Received: 14 April 1998 Received after revision: 24 September 1998 Accepted: 18 December 1998     

Acyclovir plus CMV immunoglobulin prophylaxis and early therapy with ganciclovir are effective and safe in CMV high-risk renal transplant pediatric recipients

Abstract Cytomegalovirus (CMV) infection is still a major cause of morbidity in high-risk renal transplant recipients. In the present report, we have reviewed our records of renal transplant pediatric recipients (RTPR; mean age 14.1 ± 4.9 years) since 1991, when we started a policy of CMV prophylaxis constituting high-dose oral acyclovir plus CMV hyperimmune immunoglobulins (Hlg) followed by early i.v. ganciclovir therapy in high-risk patients (i.e., CMV donor +/ recipient -). Four patients received a kidney from a living relative (LR), 2 patients had one previous transplant, and 1 had a combined liver -kidney transplant. Thirty-three patients who were negative for CMV antibodies (ab) before transplantation received a kidney from CMV ab positive donors. The immunosuppressive regimen included cyclosporin A and steroids, with the addition of azathioprine in the 4 patients who received an LR kidney. Serial assessments for CMV antigenemia (pp 65) were routinely performed for 6 months after transplantation to define CMV infection. Among the 33 CMV seronegative recipients (R -) who received the graft from a CMV seropositive donor (D +), 18 (54.5 %) experienced CMV infection, whereas among the 28 CMV R +, who received a graft from a CMV D +, 11 (39.3 %) experienced CMV infection. With regard to CMV - related symptoms, only 2 patients suffered from a CMV syndrome (fever and leukopenia in 1 patient, fever and arthralgia in the other). In no case did the spectrum of CMV disease occur; only minor symptoms were present in 7 of the remaining CMV-infected patients (fever in 6 and leukopenia in 1). Rejection episodes and renal function did not differ between CMV-infected and non-CMV-infected patients. Our experiences support the use of prophylactic acyclovir plus CMV HIg followed by early therapy with i.v. ganciclovir to combat the risk of increased morbidity in high risk RTPR.     

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.     

Randomized controlled trial of sequential intravenous and oral ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with cytomegalovirus-seropositive donors

Cytomegalovirus (CMV)-seronegative liver transplant recipients with CMV-seropositive donors have the greatest risk for CMV disease. We performed a randomized, controlled trial comparing sequential intravenous (IV) and oral ganciclovir with prolonged IV ganciclovir for long-term prophylaxis of CMV disease in these high-risk patients. Patients were initially given IV ganciclovir at a dose of 6 mg/kg per day from days 1 to 14 after transplantation. Patients then either received oral ganciclovir (1 g every 8 hr) or continued IV ganciclovir (6 mg/kg once per day on Monday-Friday of each week) from days 15 to 100 after transplantation. CMV disease occurred in 3 of 32 patients (9.3%) receiving oral ganciclovir and in 4 of 32 patients (12.5%) receiving IV ganciclovir within the first year after transplantation (P>0.2). All cases of CMV disease occurred more than 90 days after transplantation (median time of onset day +137 for oral ganciclovir and day +135 for IV ganciclovir). There were no deaths from CMV in either study group. Both oral and IV ganciclovir were generally well tolerated. These results indicate that, after induction with 14 days of IV ganciclovir, oral ganciclovir can be as effective as IV ganciclovir for long-term prophylaxis of CMV disease in high-risk CMV-seronegative liver transplant recipients with CMV-seropositive donors and eliminates the need for prolonged IV access.     

Long-term results of CMV hyperimmune globulin prophylaxis in 377 heart transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) has emerged as the most important pathogen to affect the post-operative course after heart transplantation. We performed a retrospective analysis to evaluate the efficiency of CMV hyperimmune globulin (CMVIG) prophylaxis in preventing CMV disease in aggressively immunosuppressed patients after heart transplantation. METHODS: We studied 377 heart transplant recipients who received quadruple-immunosuppressive therapy and CMVIG as sole CMV prophylaxis. The study population was categorized into 4 groups according to donor and recipient CMV serology at the time of transplantation (D+/R+, D+/R-, D-/R+, D-/R-) and was monitored for CMV immediate early antigen in peripheral blood cells, in urine sediments, and in throat washings; for the presence of serum CMV immunoglobulin M and CMV immunoglobulin G; and for clinical evidence of CMV-related symptoms. In addition, we compared the incidence of cardiac allograft vasculopathy and infection among the groups. RESULTS: During the first 5 years after transplantation, CMV disease developed in 79 patients (20.96%). Comparison among the groups showed significantly increased risk for CMV disease in allograft recipients of organs from seropositive donors (D+, 27.31%; D-, 11.33%; p = 0.0003). We observed 6 CMV-associated deaths, all in CMV-antibody-negative recipients. Additionally CMV-positive recipients had a greater incidence of cardiac allograft vasculopathy (p = 0.048), and a greater overall infection rate (p = 0.0034). CONCLUSIONS: Cytomegalovirus hyperimmune globulin administration prevents CMV disease and infection in aggressively immunosuppressed heart transplant recipients. Because fatal CMV disease in CMV-negative recipients of organs from seropositive donors could not be prevented with CMVIG alone, we recommend the additional use of prophylactic ganciclovir in this CMV-mismatched population.     

Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients

Cytomegalovirus (CMV) seronegative renal allograft recipients (R-), particularly those with a graft from a CMV-seropositive donor (D+), are at high risk for primary CMV infection. CMV resistance to antiviral oral therapy is an emerging problem in renal transplantation, prompting development of new prophylactic strategies. We retrospectively studied the 1-year posttransplantation incidence of CMV infection in high-risk renal transplant recipients, in whom polyvalent intravenous immunoglobulins (IVIg) were used as prophylaxis. Forty R- patients received immunoprophylaxis by polyvalent IVIg (0.25 g/kg weekly for 8 weeks, starting on the operative day). CMV serological tests remained negative in eight patients (20%). Eight patients (20%) had asymptomatic CMV infection while 24 (60%) developed CMV syndrome and were treated with gancyclovir (10 mg/kg/day intravenously for 3 weeks). None had CMV disease or opportunistic infection. Six patients (15%) had biopsy-proven acute rejection, which followed CMV syndrome in three cases. One-year renal allograft and patient survivals were 95% and 97.5%, respectively. Mean serum creatinine level was 124 +/- 33 micromol/L at 1 year. Clinical tolerance of IVIg was excellent, without any episode of acute renal failure. Polyvalent IVIg provides effective prophylaxis in renal transplant recipients at high risk for CMV infection and is associated with excellent 1-year allograft survival. Because of their immunomodulatory functions, IVIg may have a beneficial effect on the incidence of acute and chronic rejection and allograft survival. A randomized prospective study is required to evaluate long-term effects of CMV prophylaxis with polyvalent IVIg compared to antiviral agents in renal transplant recipients.     

Cytomegalovirus infection in seronegative patients treated with prophylaxis: case-controlled study

Primary cytomegalovirus (CMV) infection is common in infancy with approximately 90% to 95% of subjects developing antibodies against this virus. CMV seronegative renal allograft recipients generally receive this infection with a graft or with blood transfusions, showing a high morbidity and mortality. Prophylaxis in these patients has shown good results; however, the published studies have included a small number of patients. Our case-controlled study evaluated 163 kidney transplant recipients: 76 seronegatives for CMV and 87 seropositive for CMV as controls. The evaluated parameters were: CMV infection, CMV disease, renal function, and survival of the patient and graft. We studied our experience among CMV seronegative patients treated with various prophylaxis guidelines. Our conclusions were that CMV prophylaxis in seronegative patients was effective because it showed a risk of infection that was equal (or even less) than that in seropositive patients and revealed a delay in the onset of the disease. CMV seronegativity may be a positive prognostic factor for graft survival.     

肾移植术后的巨细胞病毒感染及其对急性排斥反应的影响

目的 探讨肾移植受者术后活动性巨细胞病毒（ＣＭＶ）感染的发生率、感染的原因以及ＣＭＶ感染对急性排斥反应的影响。方法 检测１８７例肾移植受者和供者术前血清抗－ＣＭＶ抗体;受者术后定期检测体内ＣＭＶ ＤＮＡ、对ＣＭＶ ＤＮＡ阳性的部分患者给予抗ＣＭＶ治疗,并比较各组排斥反应的发生率。结果 无论是供者还是受者,术前如血清抗－ＣＭＶ抗体阳性,受者术后发生活动性ＣＭＶ感染者明显增多,这些患者急性排斥反应的发     

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.     

Successful prophylaxis of cytomegalovirus disease after primary CMV exposure in liver transplant recipients.

During a 38-month period, we studied 320 liver transplants in 283 recipients (202 adults, 81 children). CMV disease was documented in 85 patients (30.0%) The major risk factor for CMV disease was primary CMV exposure (transplanting a seropositive allograft into a seronegative recipient). A total of 42 patients (14.8%) had primary CMV exposure. Twenty-one patients were historical controls, while the next 21 received prophylaxis for CMV infection in a nonrandomized trial of consecutive study groups. The regimen of prophylaxis consisted of intravenous immune globulin (IgG; 0.5 g/kg) at weekly intervals for 6 weeks and acyclovir for 3 months. CMV prophylaxis resulted in a dramatic reduction in the incidence of CMV disease (71.4% vs. 23.8%, (P less than 0.01). All cases of CMV were treated with intravenous ganciclovir (5 mg/kg b.i.d. for 14 days), with 5 patients in the control group developing recurrent CMV disease (33.3% relapse). In the 16 patients receiving prophylaxis who did not develop CMV disease, all developed positive CMV-IgG titers with the passive administration of IgG. However, none developed any evidence of CMV infection or viral shedding as assessed by IgM titers and surveillance viral cultures. Four deaths occurred (all control patients), but none were related to CMV disease. Overall patient and graft survivals after primary CMV exposure were 90.5% and 82.2%, respectively, after a mean follow-up of 14 months. Conclusion: Primary CMV exposure is a major risk factor for CMV disease in liver transplant recipients. Intravenous IgG plus acyclovir is safe and effective in preventing CMV infection and disease in this setting. Because of the scarcity of donor organs, we do not advocate protective matching to avoid primary CMV exposure but rather recommend prophylaxis to prevent CMV disease in this high-risk group.     

Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone.

BACKGROUND: Cytomegalovirus (CMV) disease was previously shown to be unaltered by a 28-day course of ganciclovir compared with placebo in seronegative recipients of hearts from seropositive donors (D+/R-). This study tests the hypothesis that a combination of ganciclovir plus CMV hyperimmune globulin (CMVIG) is more effective than ganciclovir alone for preventing acute CMV illness and its long-term sequelae. METHODS: The study population receiving CMVIG (n=80) included 27 heart transplant recipients (D+/R-) and 53 heart-lung and lung transplant recipients (R+ and/or D+). Each group was matched with historical controls who underwent transplantation within the preceding 2-3 years. Outcome measures compared were as follows: 3-year incidence of CMV disease; fungal infection; acute rejection; survival; rates and severity of transplant coronary artery disease (in heart patients) defined by intimal thickness (ultrasound) and coronary artery stenosis (angiographic); and incidence and death from obliterative bronchiolitis defined by pathological criteria on endobronchial biopsy specimens (in heart-lung/lung patients). RESULTS: Patients treated with CMVIG had a higher disease-free incidence of CMV, lower rejection incidence, and higher survival rate compared with the patients treated with ganciclovir alone. The coronary artery intimal thickness and the prevalence of intimal thickening were lower in the patients receiving CMVIG. Heart-lung and lung transplant patients treated with CMVIG had lower incidences of obliterative bronchiolitis and death from obliterative bronchiolitis and longer survival compared with the patients treated with ganciclovir alone. CONCLUSIONS: CMVIG plus ganciclovir seems to be more effective that ganciclovir alone for preventing the sequelae of CMV infection. A prospective randomized study is required to confirm these observations.     

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.     

Failure of ganciclovir prophylaxis to completely eradicate CMV disease in renal transplant recipients treated with intense anti-rejection immunotherapy

Ganciclovir prophylactic regimens have been shown to be effective in renal transplant recipients at risk for primary (donor seropositive/recipient seronegative) and secondary (recipient seropositive) cytomegalovirus (CMV) disease. However, in addition to serologic factors, the type and intensity of the administered immunosuppression is a strong risk factor for CMV disease. Since January 1995, we have utilized a potent immunosuppressive protocol selectively in recipients at high risk for immunologic graft loss, defined as retransplant recipients, recipients with delayed graft function, non-Caucasian recipients, and recipients suffering from acute rejection. Between January 1995 and December 1996, 110 consecutive renal transplants were performed in recipients who were either CMV seropositive or received an allograft from a CMV-seropositive donor. All recipients received ganciclovir prophylactic therapy for 3 months post-transplant. Group I (N = 43) consisted of recipients at high-immunologic risk for graft loss as defined above. These recipients were treated with an intense anti-rejection immunotherapeutic regimen consisting of Cellcept, Neoral, and prednisone, with the frequent addition of antilymphocyte antibody therapies and intravenous methylprednisolone. The remaining 67 recipients (group II) were treated with a less intense immunotherapeutic regimen consisting of azathioprine, Neoral, and prednisone. The incidence and severity of CMV disease and the patient and allograft survival were compared. The incidence of CMV syndrome was greater in group I (28%) compared with group II (7%), and was statistically significant (p < 0.05). The 1-yr patient and graft survival were similar, 95 and 91%, respectively, for group I compared with 97 and 97%, respectively, for group II. These data suggest that 3 months of ganciclovir prophylactic therapy is significantly less effective for the prevention of CMV disease in renal transplant recipients at high risk for acute rejection treated with an intense immunotherapeutic regimen. These data suggest that more effective prevention of CMV disease in these high-risk recipients will require the addition of other anti-viral agents, such as immunoglobulin preparation to the prophylactic regimen.     

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients

Cytomegalovirus (CMV) infection and disease are potential risk factors for acute allograft rejection in renal transplant recipients. The present study specifically addresses this issue. From October 1994 to July 1997, 477 consecutive renal allograft recipients (397 first transplants and 80 retransplants) were included in the study. CMV infection (cytomegalovirus pp65 antigen in leukocytes) and disease (infection and clinical symptoms or signs of disease) were examined prospectively for 3 months. No CMV prophylaxis was given, and CMV disease was treated with intravenous (i.v.) ganciclovir. The retransplantation of four patients transplanted twice during the study and 22 patients receiving kidneys from human leucocyte antigen (HLA)-identical siblings were excluded from statistical analysis. Rejections were evaluated clinically [277(61%)] and 173 (38%) also had a biopsy verified rejection. CMV infection occurred in 64% of the patients and 24% experienced CMV disease. In a multiple time-dependent Cox analysis, CMV infection and CMV disease were independent significant predictors for clinical acute rejections, RR = 1.6 (1.1-2.5, p = 0.02) and RR = 2.5 (1.2-5.1, p = 0.01), respectively. Among 173 patients with biopsy verified rejection, 72% of the patients had tubulointerstitial rejection whereas 28% had a vascular rejection. CMV disease, but not CMV infection was a predictor of tubulointerstitial rejection, RR = 3.1 (1.1-9.3, p = 0.04). CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV disease is an independent risk factor for biopsy verified acute tubulointerstitial rejection in kidney allograft recipients.