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Background: Cytomegalovirus (CMV) infection is associated with higher non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). But the preferred drug for preventing cytomegalovirus infection is still controversial. We evaluate the efficacy, safety, and cost-effectiveness of antiviral agents based on the most recent studies., Methods: A pairwise and network meta-analysis was conducted to obtain direct and indirect evidence of antivirals. The cost of allo-HSCT recipients in a teaching hospital was collected, and a cost-effectiveness analysis using a decision tree combined with Markov model was completed from the perspective of allo-HSCT recipients over a lifetime horizon., Results: A total of 19 RCTs involving 3565 patients (8 antivirals) were included. In the network meta-analysis, relative to placebo, letermovir, valacyclovir, and ganciclovir significantly reduced CMV infection incidence; ganciclovir significantly reduced CMV disease incidence; ganciclovir significantly increased the incidence of serious adverse event; none of antivirals significantly reduced all-cause mortality. Based on meta-analysis and Chinese medical data, the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) saved for maribavir, acyclovir, valacyclovir, ganciclovir, and letermovir relative to placebo corresponded to US$216 635.70, US$11 590.20, US$11 816.40, US$13 049.90, and US$12 189.40, respectively. One-way sensitivity analysis showed the most influential parameter was discount rate. The probabilistic sensitivity analysis indicated a 53.0% probability of letermovir producing an ICER below the willingness-to-pay threshold of US$38 824.23/QALY. The scenario analysis demonstrated prophylaxis with letermovir is considered cost-effective in the United States., Conclusions: Currently, letermovir is an effective and well-tolerated treatment for preventing CMV infection, and it might be a cost-effective choice in allo-HSCT recipients in China., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Most pediatric liver transplantation (LT) centers administer long courses of prophylaxis against cytomegalovirus (CMV) without evidence of benefit and with significant drug exposure and costs. We aimed at evaluating overall outcomes, direct and putative indirect effects of CMV, possible impact of viremia and risk factors for CMV infection in pediatric LT recipients managed with ganciclovir-based preemptive therapy (PET)., Methods: The records of all the children who underwent LT between 2008 and 2014 were retrospectively analyzed., Results: One hundred children were included. Three children had CMV disease; no CMV-related death or graft loss was recorded. The only identified risk factor for CMV infection was the donor/recipient serostatus (odds ratio, 17.23; 95% confidence interval, 1.88-157.87; P = 0.012), while viremia per se did not worsen LT outcomes, such as the incidence of acute rejection, Epstein-Barr virus infection, sepsis, biliary and vascular complications, nor graft dysfunction/loss or death at 3 and 5 years after LT. When compared with a historical cohort of children receiving ganciclovir prophylaxis, PET did not differ from prophylaxis for any of the selected outcomes, but was rather associated with lower antiviral drug exposure (6.4 ± 13 days vs 38.6 ± 14 days, P < 0.0001) and cost per patient (2.2 ± 3.9 k&OV0556; vs 6.6 ± 8.2 k&OV0556;, P = 0.001)., Conclusions: PET is effective in controlling CMV in children receiving LT, with lower costs and lower exposure to antivirals.

Background: Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs., Methods: Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity., Results: Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in SOT (P = 0.003). Doses of ganciclovir or valganciclovir were low in 10 (26%) of 39 at some time before switching to foscarnet. Renal dysfunction occurred in 20 (51%) of 39 by end of treatment and in 7 (28%) of 25 after 6 months., Conclusions: Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents., Competing Interests: Other than as specified above, the authors declare no conflicts of interest.

Background: Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection., Methods: We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity., Results: While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R-) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 ± 3.4 vs. 30.1 ± 4.7 mL/min per 1.73 m(2) in the preemptive therapy cohort, P < 0.05).CMV replication was associated with a more pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m(2) at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia., Conclusion: Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome.

Background: Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR)., Methods: Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed., Results: Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar., Conclusions: Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir may provide a significant cost avoidance benefit.

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

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

Background: The role of valganciclovir in the prevention of cytomegalovirus (CMV) disease in high-risk seropositive transplant patients is not known., Methods: We prospectively followed 301 seropositive solid organ transplant recipients to assess the efficacy and safety of valganciclovir (VGCV) in the prevention of CMV disease in high-risk patients. Asymptomatic patients with an antigenemia test >or=25 positive cells/2x10(5) polymorphonuclear cells received valganciclovir 900 mg twice a day as preemptive therapy until resolution of antigenemia (minimum 14 days). Additionally, patients treated with antilymphocytic drugs for more than 6 days received prophylaxis with VGCV 900 mg once a day during 90 days. Mean follow-up was 14 months (range 6-20 months)., Results: Thirty-eight patients received VGCV; 24 as preemptive therapy and 14 due to the use of antilymphocytic drugs. No patient developed CMV disease during the follow-up. Viral load (antigenemia) decreased a mean of 78% from baseline after 7 days of VGCV therapy (P=0.024) and 98% at day 14 (P=0.029). Two patients showed a relapse of the antigenemia test >or=25 positive cells and were successfully treated with a repeated course of VGCV. Leukopenia (<2500/mm3) developed in 3/24 (12.5%) recipients in the preemptive therapy group and required to discontinuing the drug in one of them., Conclusions: VGCV is safe and highly efficacious in the prevention of CMV disease in high-risk seropositive organ transplant recipients.

Two thoracic organ-transplant recipients with persistent cytomegalovirus infection developed morphologic abnormalities in their circulating neutrophils while receiving either ganciclovir or its prodrug valganciclovir. Neither patient was receiving concomitant treatment with mycophenolate mofetil or azathioprine. In both patients, the morphologic abnormalities preceded the development of neutropenia and bone-marrow hypoplasia. The morphologic changes most likely reflected interference of DNA polymerization within bone marrow progenitor cells. The changes resolved completely after the drug was withdrawn.

Background: Both oral ganciclovir and valacyclovir decrease the incidence of cytomegalovirus (CMV) disease after renal transplantation. Moreover, valacyclovir has been shown to reduce the risk of acute rejection. Our study was designed to compare the efficacy and safety of oral ganciclovir and valacyclovir in the prophylaxis of CMV disease after renal transplantation., Methods: A total of 83 patients were prospectively randomized to 3-month treatment with oral ganciclovir (3 g/day, n=36, GAN) or oral valacyclovir (8 g/day, n=35, VAL). A control group (DEF, n=12) was managed by deferred therapy., Results: No differences were found in demography, immunosuppression, or donor/recipient CMV serology. The 12-month incidence of CMV disease was 67% in the DEF group compared with 6% in the GAN group and 3% in the VAL group (P<0.001 GAN or VAL vs. DEF; P=0.575 GAN vs. VAL). The biopsy-confirmed acute rejection rate at 12 months was 12% in the VAL group compared with 34% in the GAN group (P=0.030) and 58% in the DEF group (P<0.001). The difference between the GAN and DEF groups was not significant (P=0.087). The average CMV-associated costs per patient were $3,072, $2,906, and $4,906 in the GAN, VAL, and DEF groups, respectively., Conclusions: Valacyclovir and oral ganciclovir are equally effective in the prevention of CMV disease after renal transplantation. Both regimens are cost-effective. Valacyclovir is associated with a significantly reduced risk of acute rejection compared with both ganciclovir prophylaxis and deferred therapy.

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.

Background: With the development of sensitive tests to detect cytomegalovirus (CMV) viremia, preemptive approaches become a reasonable alternative to general CMV prophylaxis. We performed a randomized trial comparing pp65-antigenemia guided preemptive therapy using oral ganciclovir with symptom-triggered intravenous ganciclovir treatment., Methods: Eighty-eight of 372 liver transplant recipients developed antigenemia early after orthotopic liver transplantation. Twenty-eight symptomatic patients with antigenemia were excluded from randomization and treated with intravenous ganciclovir. Sixty pp65-antigen-positive asymptomatic patients were randomized to receive either oral ganciclovir 3x1 g/day for 14 days (group 1) or no preemptive treatment (group 2). Patients that developed CMV disease were treated with intravenous ganciclovir 2x5 mg/kg body weight for 14 days. The high-risk (Donor+/Recipient-) patients were equally distributed in the two study groups., Results: Three of 30 (10%) patients on oral ganciclovir developed mild to moderate CMV disease compared with 6/30 (20%) patients in the control group. In the Donor+/Recipient- patients, the incidence of CMV disease was 1/6 and 3/7. All disease episodes resolved after intravenous treatment. The 1- and 3-year patient and organ survival was the same in the study groups and in the patients with or without CMV infection. No deaths related to CMV occurred., Conclusions: The positive predictive value of pp65-antigenemia for the development of CMV disease was very low, and, in 28/88 patients (32%), antigenemia did not precede symptoms. Therefore, pp65-antigenemia is of limited value in deciding on the timing and need for ganciclovir therapy after liver transplantation.

Background: Ganciclovir (GCV) is effective for prevention of cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity. There is little information on the effect of GCV on a human fetus., Methods: The chart of a liver transplant recipient who received oral GCV during the first trimester was reviewed as was the published literature., Results: There was no evidence of teratogenicity in the baby or in a case reported elsewhere., Conclusions: GCV has been used in a few female transplant recipients without untoward effects. The still uncertain risk of short term and long term teratogenicity, however, must be weighed against the risk of CMV disease in the recipient and the development of congenital CMV in the baby.

Background: The emergence of a ganciclovir (GCV)-resistant human cytomegalovirus (HCMV) strain in a heart transplant recipient (HTR) coinfected by multiple HCMV strains was investigated., Methods: A HTR with primary HCMV infection was treated with three induction courses of intravenous GCV followed by a 2-month maintenance treatment with oral GCV. HCMV antigenemia, viremia, and leukoDNAemia levels were monitored. GCV susceptibility was analyzed by an immediate-early antigen plaque reduction assay and by a rapid screening assay performed using peripheral blood leukocytes (PBL) as viral inoculum. The viral population in blood was investigated by restriction analysis of multiple genome regions. UL97 and UL54 genes were sequenced in parallel in both HCMV isolates and the relevant PBL samples. A rapid molecular assay for detection and quantitation of the GCV-resistant mutant was developed., Results: The emergence of a GCV-resistant UL97 mutant (Cys-607 --> Tyr) was responsible for treatment failure during oral GCV therapy. The genetic analysis of the HCMV population showed the sequential appearance in blood of two unrelated strains (referred to as A and B). Strain A most likely derived from the transplanted organ and strain B from a subsequent blood transfusion. The resistant variant (Br) emerged from strain B and became predominant "in vivo" under the GCV pressure. However, after foscarnet administration, the resistant mutant disappeared in viral isolates, whereas it was still present as a minor proportion in PBL samples., Conclusion: (a) Oral GCV may select resistant strains in transplanted patients; (b) results of the rapid screening assay were clinically useful for shifting to an alternative treatment, thus avoiding the appearance of HCMV disease; (c) virus isolation may not be the most reliable approach to detection of HCMV drug-resistant strains; (d) a novel molecular assay for rapid detection of UL97 Cys-607 --> Tyr mutation directly in clinical specimens was developed, allowing earlier "in vivo" detection of the resistant mutant.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.