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.     

Impact of cytomegalovirus match on survival after cardiac and lung transplantation

Acute cytomegalovirus (CMV) disease and indirect effects caused by the virus alter the outcome after solid organ transplantation. Long-term results after 54 lung and 139 cardiac transplants at a single center have been retrospectively analyzed with regard to CMV status. Standard CMV prophylaxis consisted of ganciclovir for 100 days. Lung recipients were pretransplant CMV negative in 32 per cent as compared to heart recipients with 23 per cent. Patient survival after mismatch transplants (donor positive, recipient negative) was significantly reduced as compared to the other match groups (42% vs 76% at five years, P = 0.01). In heart recipients, CMV positive patients receiving a CMV negative graft showed best survival, whereas in the group of lung recipients negative/negative matched transplants produced best results. In both groups, CMV negative grafts had a better outcome than CMV positive grafts, and a survival difference between heart and lung recipients was only observed in recipients of a CMV positive grafts. Despite ganciclovir prophylaxis, CMV match remains an important factor for survival following heart and, even more profoundly, lung transplantation. Because survival was least favorable in the mismatched group, prophylactic regimens warrant improvement. For CMV negative lung recipients, CMV matching might be considered.     

Delayed-onset primary cytomegalovirus disease after liver transplantation.

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor-positive/recipient-negative (D+/R-) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R- liver transplant recipients who received antiviral prophylaxis. Sixty-seven CMV D+/R- liver transplant recipients (mean age+/-standard deviation: 49.5+/-11.4 years; 75% male) received oral ganciclovir [n=9 (13%)] or valganciclovir [n=58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91-100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed-onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P=0.01) and younger age at transplant (P=0.03) were associated with an increased risk, whereas diabetes mellitus (P<0.001) was significantly associated with a lower risk of delayed-onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow-up period of 3.31 (range: 0.8-5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R- liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed-onset primary CMV disease.     

Effect of cytomegalovirus prophylaxis with acyclovir on renal transplant survival

It is recognized that cytomegalovirus (CMV) infection in transplant recipients may lead to graft loss. Prophylaxis with acyclovir has therefore gained widespread acceptance, but the debate on whether this intervention improves long term graft survival continues. All patients who received renal grafts at the National Renal Transplant Centre, Dublin, between January 1992 and December 1999 were retrospectively analyzed. During this time period, patients who were CMV positive and/or had received grafts from CMV-positive donors were administered prophylactic oral acyclovir 800 mg thrice daily, adjusted for calculated creatinine clearance, from the first day post-transplantation. This treatment was continued for three months unless the graft failed or the patient developed CMV disease or died. Graft and patient outcomes were compared in recipients who received acyclovir with those who did not. Over the study period, 935 patients received renal transplants in our center, of whom 487 were administered acyclovir. The incidence of CMV disease was 3.3 cases per 100 patients per annum in those who required prophylaxis. Despite prophylaxis, graft outcomes were found to be significantly worse (p value < 0.001) in the group that qualified for acyclovir. We conclude that acyclovir provides incomplete protection from the negative impact of CMV on graft survival.     

Long-term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Abstract: Background: Information is limited on long‐term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. Methods: We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two‐wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV‐mismatched patients (R?D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. Results: The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R?D+ patients (p < 0.0001). Over 4.3 yr of follow‐up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. Conclusions: The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R?D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.     

Low-dose valaciclovir and cytomegalovirus immunoglobulin to prevent cytomegalovirus disease in high-risk renal transplant recipients

Background: Cytomegalovirus (CMV) remains an important cause of disease in renal transplant recipients. Prophylaxis is effective in reducing disease; however, the optimal regimen remains uncertain. We assessed the efficacy of low‐dose valaciclovir (3 months) and intravenous CMV immunoglobulin in the prevention of CMV disease in CMV‐negative recipients of kidneys from CMV‐positive donors (D+/R?). Methods: A single‐centre, retrospective study examining the incidence of CMV disease and patient and graft survival in all patients transplanted between October 2000 and November 2004. Results: Among 203 renal transplant recipients, 46 were D+/R? (22.7%) and received prophylaxis. Of the 203 recipients, 21 (10.3%) developed CMV disease over a four‐year follow‐up period. Within the D+/R? group, CMV disease occurred in 15.2% of patients at 6 months (7/46), and 21.7% at 4 years (10/46). Of the 10 D+/R? patients who developed CMV disease, six were inadvertently on a dose of valaciclovir below that dictated by protocol arising from a failure to increase dosage in parallel with improving recipient renal function. In the D+/R? recipients where the protocol was adhered to, the incidence of CMV disease was 5% (2/40) at 6 months, and 10% (4/40) at 4 years. Conclusion: Low‐dose valaciclovir with CMV immunoglobulin was as efficacious in preventing CMV disease as other published regimens, including those with full‐dose valaciclovir and valganciclovir. There was a low incidence of CMV disease beyond 6 months. Outcomes could be improved by ensuring appropriate dose adjustment following changes in renal function.     

An analysis of cytomegalovirus infection and HLA antigen matching on the outcome of renal transplantation.

Eighty-five recipients and donors of renal allografts were examined for evidence of cytomegalovirus infection before and repeatedly after transplantation. The recipients were also divided into two group on the basis of HLA antigen matching. Better allograft survival was noted in patients well matched for HLA antigens (0-2) mismatched antigens) compared to those poorly matched (three or more antigens mismatched), and in patients free of cytomegalovirus compared to those infected. Cytomegalovirus infection had a more marked influence on allograft survival than did HLA antigen matching. The differing rates of success of transplantation, apparently dependent on blood relationship between donor and recipient, have been assumed largely to be due to inherited factors. This study, however, revealed an important factor to be the disparate incidence of cytomegalovirus infection in sibling, parental, and cadaveric categories of transplantation. The mechanism of this disparity can be explained on the basis of the incidence of latent CMV infection in the recipients and various categories of kidney donors.     

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.     

Double-blind, placebo-controlled trial of human lymphoblastoid interferon prophylaxis of cytomegalovirus infection in renal transplant recipients.

We have conducted a double-blind, placebo-controlled trial of human lymphoblastoid interferon prophylaxis of cytomegalovirus (CMV) infection in 74 renal transplant recipients. Interferon (3 x 10(6) units was given thrice weekly for the first 6 weeks, then twice weekly for a further 8 weeks. During the period of interferon therapy, the incidence of CMV excretion was lower in the interferon group (28% versus 50%, P = 0.065), mainly due to a significant reduction of CMV reactivation (9% versus 56%, P = 0.02). However, for the whole study period (including the follow-up period after interferon therapy), there was no difference in the incidence of CMV excretion (44% versus 53%). The onset of CMV excretion was delayed (8.2 +/- 0.8 to 20.9 +/- 5.5 weeks, P = 0.04). The duration of CMV excretion was also reduced (11.1 +/- 3.1 to 29.4 +/- 5.7 weeks, P = 0.008). The number of positive CMV isolates from urine and saliva was significantly less in the interferon group. There was no difference in the site of CMV excretion. Of the patients in the treatment group who excreted CMV, 43% developed disease as compared to 63% in the control group (difference not significant). There was also no significant difference in the severity of the CMV infection between the two groups. Benefit appears to be restricted to seropositive recipients of seronegative kidneys. The interferon regime used in this study was well tolerated, with mild fever being the only reported side-effect. No patient had to stop therapy because of toxicity. The incidence of rejection and graft loss was not different between the two groups.     

Mycophenolate mofetil does not modify the incidence of cytomegalovirus (CMV) disease after kidney transplantation but prevents CMV-induced chronic graft dysfunction.

Ganciclovir, which is used to treat cytomegalovirus (CMV) infection, has been shown in rodent models to abolish CMV-mediated chronic cellular damage and endothelial cell proliferation; when associated with mycophenolate mofetil (MMF), it has been shown to increase its anti-herpes virus activity. This study tested the hypothesis that kidney graft recipients who received antirejection prophylaxis with MMF and who were treated with ganciclovir for a declared CMV disease could be protected from chronic graft dysfunction. Investigated was the impact of ganciclovir-treated CMV diseases in consecutive first kidney recipients according to their immunosuppressive therapy. The azathioprine (Aza)-treated group (Aza group) included 319 patients. The MMF-treated group (MMF group) included 126 patients. CMV disease was clinically defined and confirmed by virological proof of CMV infection and was treated for at least 14 d with ganciclovir. Despite having the same incidence (21.6% in the Aza group versus 24.6% in the MMF group) and severity, CMV disease was significantly associated with graft loss independent of acute rejection episodes or other factors when tested in a Cox proportional model in the Aza group only (P < 10(-4)). It was shown for the first time that patients whose CMV disease is treated with ganciclovir while they are on MMF therapy are protected from the long-term deleterious consequences of CMV disease on graft survival, independent of acute rejection. It is suggested that the enhanced anti-herpes virus activity of ganciclovir by MMF could contribute to this reported effect, which may represent a significant contribution of MMF efficacy to graft survival.     

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.     

Risk factors for cytomegalovirus infection and disease in renal transplant recipients: HLA-DR7 and triple therapy

In a prospective study, an analysis of risk factors for the development of cytomegalovirus (CMV) infection and disease was performed on 77 renal allograft recipients. Twenty-five out of the 77 recipients (32%) had a CMV infection. Twenty-two of the recipients received triple immunosuppressive therapy (cyclosporin A, prednisolone, and azathioprine) while the remaining 55 received standard therapy (cyclosporin A and prednisolone). In 23 recipients (30%) acute rejection was diagnosed and the first positive parameter of infection occurred 22 days after rejection therapy. Infection occurred in 10 out of 18 HLA-DR7-positive recipients (56%) and in 15 out of 59 HLA-DR7-negative recipients (25%; P< 0.02). In multiple regression analysis, HLA-DR7 was found to be a significant predictor of CMV infection (P< 0.005). CMV disease was diagnosed in only 9 out of 25 recipients with an acute infection. Six recipients (67%) with CMV disease received triple therapy for maintenance immuuosuppression; this was significantly correlated to CMV disease (P< 0.05) as compared to three recipients (33%) with CMV disease maintained with standard therapy. Our data suggest that HLA-DR7-positive recipients are more susceptible to CMV infection and that CMV disease is associated with triple immunosuppressive therapy.     

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

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

Cytomegalovirus disease after prophylaxis with oral ganciclovir in renal transplantation: the importance of HLA-DR matching

This study assessed the incidence of cytomegalovirus (CMV) disease and associated outcomes after oral ganciclovir prophylaxis in renal transplantation. A retrospective analysis was performed of all adult renal transplant recipients at a single transplant center transplanted between August 16, 1996, and December 31, 2000. CMV disease prophylaxis included ganciclovir 1000 mg orally thrice daily prescribed for 90 d in D-/R+ cases and 180 d in D+/R- and D+/R+ cases. Forty (9.1%) of 470 patients studied were diagnosed with CMV disease, which varied significantly by CMV serostatus and number of HLA-DR matches. The highest incidence of disease, 26.2%, was in D+/R- patients with zero HLA-DR matches. Five-year graft survival was 56.8% with CMV disease compared with 79.1% without (P < 0.001). Five-year graft survival with CMV disease was 75.9% with one or two HLA-DR matches versus 16.2% with zero HLA-DR matches (P < 0.001). CMV remains an important factor in long-term graft survival after oral ganciclovir prophylaxis. However, we have observed that the adverse impact of CMV disease on graft survival is apparent only in patients with zero HLA-DR matches. These results call for the development of new CMV disease prophylaxis and treatment strategies in patients with zero HLA-DR matches. In addition, organ allocation policies discouraging combining CMV-seropositive donors and zero HLA-DR matches may be worth consideration.     

The interaction between the Lewis blood group system and HLA-matching in renal transplantation

A retrospective study was initiated to investigate the influence of recipients' Lewis subtype and HLA-matching on cadaveric kidney graft outcome. A total of 1111 patients receiving a first cadaveric kidney graft were analyzed. No difference in one-year graft survival was found between Lewis-negative (73%, n = 133) and Lewis-positive (73%, n = 978) recipients. Further subdivision of the study group into HLA-A,-B well-matched (0 or 1 mismatches [MM]) and poorly matched (2, 3, or 4 MM) revealed a strong deleterious effect of HLA-A,-B mismatching in the Lewis-negative group only. One year graft survival in Lewis-negative HLA-A,-B poorly matched (2, 3, or 4 A,B MM) patients was 60% (n = 67) versus 86% (n = 66) in the Lewis-negative HLA-A,-B well-matched (0 or 1 A,B MM) group (P = 0.004). For the Lewis-positive group the one-year graft survival rates were 72% (2, 3, or 4 A,B MM; n = 498) and 74% (0 or 1 A,B MM; n = 480), respectively (P = n.s.). The additional beneficial effect of HLA-DR matching again turned out to be strongest in the Lewis-negative group. In Lewis-negative, HLA-DR (0 MM) and -A,-B well-matched recipients (n = 36) graft survival was 94% versus only 64% in the Lewis-negative, DR matched, A,-B mismatched (2, 3, or 4 A,B MM) group (n = 25; P = 0.09). In the Lewis-positive, HLA-DR 0 mismatched group the one-year survival rates were 78% (0 or 1 A,B MM; n = 240) and 73% (2, 3, or 4 A,B MM; n = 253), respectively (P = 0.05). Our data suggest that donor recipient selection should not be based on Lewis matching per se. However, since Lewis-negative patients are at high risk of graft failure when receiving HLA mismatched kidneys, they should preferentially receive optimally HLA matched grafts.     

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

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

Association of glycoprotein B and immediate early-1 genotypes with human leukocyte antigen alleles in renal transplant recipients with cytomegalovirus infection

BACKGROUND: Numerous risk factors for cytomegalovirus (CMV) infection or disease, or both, such as serostatus of donor and recipient, immunosuppressive regimen, or intensity of viral load, have been identified in renal transplant recipients. Additional parameters may be involved, notably, genetic variability of both host and virus, which could modulate the efficacy of the immune response. METHODS: Active CMV infection was analyzed retrospectively in 634 renal transplant recipients, according to human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR alleles; CMV serostatus; presentation of the disease; and variations in the coding sequences of glycoprotein (g) B and IE1 proteins. RESULTS: Active infection occurred in 141 of 634 patients: seropositivity of the donor and the recipient were identified as risk factors. Patients carrying the HLA-A11, HLA-A32, or HLA-DR11 allele developed active infection more frequently, whereas none of the patients with the HLA-B16 or HLA-B55 allele was actively infected. Significant independent associations between some genotypes and particular HLA alleles were observed: gB1 was more frequent in the HLA-A24 or HLA-B7 context and underrepresented in patients with HLA-DR11; gB2 was more frequent in HLA-A32 or HLA-DR11 carriers; and an increased frequency of gB3 was observed in the HLA-A29 context. Considering the IE1-2 genotype, increased frequency was noted for HLA-A3 carriers, whereas this type was underrepresented for patients with the HLA-DR11 allele. CONCLUSION: Data strongly suggest that differential presentation of polymorphic gB or IE peptides by HLA molecules or differential recognition by host CD8+ and CD4+ T lymphocytes, or both, should modulate immunologic response and then CMV pathogenesis in renal transplant patients.     

Effect of primary and recurrent cytomegalovirus infections upon graft and patient survival after renal transplantation.

One hundred sixty-four patients were prospectively studied for evidence of cytomegalovirus (CMV) infection after renal transplantation to determine the effect of primary and recurrent CMV infection on early graft and patient survival. Primary infections occurred in 62% (21 of 34) of pretransplant seronegative recipients and recurrent infection infection in 93% (121 of 130) of seropositive recipients. Symptomatic infections occurred in 81% (17 of 21) of primarily infected and 31% (37 of 121) of recurrently infected recipients. CMV infections (determined by initial virus excretion) occurred in 86% of the primarily infected and 96% of the recurrently infected symptomatic recipients by the 9th post-transplant week. In contrast, only 53% of nonsymptomatic recipients excrete virus by the 9th week. Primarily infected recipients experienced a significantly lower graft survival at 6 months than uninfected seronegative or recurrently infected patients. However, there was no significant difference in patient or graft survival at 1 year. Recipients who developed recurrent symptomatic infections had a significantly lower graft and patient survival than those recipients who developed nonsymptomatic recurrent infections (P less than 0.0002 patient survival and P less than 0.001 graft survival at 12 months).     

24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course

BACKGROUND: Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among kidney recipients. The highest risk of CMV infection occurs in CMV-naive recipients of kidneys from seropositive donors (D+/R-). Optimal CMV prophylaxis is not established. This prospective cohort study compared the safety and efficacy of prophylaxis with 12 versus 24 weeks of oral ganciclovir. METHODS: We prospectively administered 24 weeks ganciclovir to 31 D+/R- recipients. The control group comprised 39 patients transplanted in the immediately preceding era who received a 12-week course of prophylaxis. All patients received cytolytic therapy within the first month, as well as a tacrolimus-based maintenance regimen. A logistic regression model was fit to examine the relationship between 24 weeks ganciclovir prophylaxis and the odds of developing CMV infection by one year. RESULTS: Groups were matched, though the 12-week cohort had more delayed graft function than their 24-week counterparts (45% vs. 29%, P=0.04). CMV infection occurred in 31% and 7% patients in the 12-week and 24-week groups, respectively (P相似文献   

Incidence and morbidity of cytomegalovirus disease associated with a seronegative recipient receiving seropositive donor-specific transfusion and living-related donor transplantation. A multicenter evaluation

This retrospective study was conducted to identify the frequency of cytomegalovirus (CMV) disease in seronegative recipients of donor-specific transfusion (DST) and living-related donor (LRD) kidneys from seropositive donors. A total of 151 LRD transplants (TX) were performed at six transplant centers over a 3-year period. A total of 33 patients were identified as having been seronegative (pre-TX) for CMV, yet they had DST and a TX from a seropositive LRD. Of these patients, 12 (36.4%) seroconverted within the first 6 months post-TX and developed clinical CMV disease. Additional patients seroconverted, but did not have evidence of clinical disease and were not tested further. All TX centers, with the exception of one, had seronegative patients that became ill after receiving a seropositive DST/LRD TX. Six patients manifested their disease as a febrile illness with leukopenia and liver enzyme elevations, four had pneumonitis, and two developed CMV ulcerations of the colon (one of whom died from resultant sepsis). Of the 36 seronegative patients who received seronegative DST/LRD TX none became ill with CMV disease. Of the 72 seropositive patients who received DST/LRD TX, only 2 (2.8%) developed CMV illness (one, seropositive into seropositive, the other, seronegative into seropositive). Of the 33 seronegative patients receiving seropositive DST/LRD TX, 17 received antilymphocyte preparations (ALP), and 8 of these became ill (47.1%). Of 16 patients not receiving ALP, 5 (31.3%) developed clinical CMV illness. Of the 33 patients who were identified as having been seronegative for CMV yet received seropositive DST/LRD TX, the 12 who did develop CMV illness had two graft losses, one death, and a serum creatinine for the remaining 9 patients of 2.3 +/- 1.6 at last follow-up. The remaining 21 patients who developed no illness had a serum creatinine of 1.3 +/- 0.6 with no graft losses at the last follow-up. This evidence suggests that a prospective TX recipient who is seronegative for CMV who receives DST/LRD TX from a seropositive family member has a significant risk for developing morbidity related to clinical CMV illness.