Project description:Importance:Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. Objective:To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. Design, Setting, and Participants:Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. Interventions:Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). Main Outcomes and Measures:The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. Results:Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). Conclusions and Relevance:Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT01552369.

Project description:Abstract Background Current guidelines preferentially recommend valganciclovir (VGCV) prophylaxis over PET in most D+R? organ transplant populations, but adequately powered direct comparative clinical trials are lacking. Methods D+R? LTR were randomly assigned (1:1, stratified by site and T-cell depleting induction) to receive either PET (weekly plasma CMV DNAemia at central laboratory for 100 days, with VGCV 900 mg bid for DNAemia at any level, until two consecutive negative weekly tests) or prophy (VGCV 900 mg qd for 100 days). The primary outcome was CMV disease by 12 months as adjudicated by an independent, blinded, endpoint committee in ITT population. Secondary outcomes were opportunistic infections (OIs) (invasive fungal and bacterial), neutropenia (ANC < 1000/µL), acute rejection, graft loss, and mortality assessed at12 months. Results From October 2012 to June 2017, 205 patients were randomized at six centers; 100 to PET, 105 to prophy. The incidence of CMV disease was 9% (9/100) in PET and 19% (20/105) in prophy (P = 0.039) with majority of difference due to post-prophylaxis disease: 6% in PET vs. 17% in prophy (P = 0.027). CMV disease included syndrome in 55% (16/29) and end-organ in 45% (13/29), with similar proportions in two groups. Secondary outcomes were not different for PET and prophy groups: OIs (19% vs. 21%), neutropenia (34% vs.. 28%), acute rejection (27% vs. 27%), graft loss (2% vs. 2%), and mortality (10% vs. 6%), respectively, P > 0.05 for all comparisons. Mortality at last follow-up (median 3.2 years) was not different for PET vs. prophy (14% vs. 18%, P = 0.43). Conclusions PET significantly reduced the incidence of CMV disease compared with prophy in D+R- LTR, and was associated with similar other clinical outcomes. Current guidelines should be revised to recommend PET over prophylaxis in this setting, and similar trials conducted in other D+R? transplant populations. (Funded by NIAID; ClinicalTrials.gov# NCT01552369.) Disclosures D. Winston, Merck: Investigator, Research support. Chimerix: Investigator, Research support. Shire: Investigator, Research support. Gilead: Investigator, Research support. Oxford Immunotech: Investigator, Research support. G. M. Lyon III, Shire: Investigator, institutional research support. Hookipa: Investigator, institutional research support. Merck: Investigator, institutional research support. F. P. Silveira, Shire: contracted clinical research, site investigator. A. P. Limaye, Merk: Consultant and Investigator, Consulting fee and Research grant. Astellas Pharma Inc.: Consultant and Investigator, Consulting fee. Helocyte Inc.: Consultant, Consulting fee.

Project description:Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC24) of 40 to 50 μg·h/mL. Full-length UL54 and UL97 were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of <40 mL/min were higher than specified by guidelines, and they were lower for recipients with creatinine clearance of ≥40 mL/min. The mean ganciclovir AUC24 was 33 ± 13 μg·h/mL, and 82% of subjects did not attain the therapeutic target. Pharmacokinetic simulations showed that the guidelines similarly could not attain the therapeutic target in 79% of individuals. Cytomegalovirus breakthrough occurred in 6% (3/50) of recipients, while 12% (6/50) developed late-onset infection. The mean AUC24s of recipients with (n = 3) and without (n = 47) infection were not significantly different (P = 0.528). However, one recipient with an AUC24 of 20 μg·h/mL acquired two UL97 ganciclovir resistance mutations. Current prophylaxis guidelines resulted in subtherapeutic ganciclovir exposure in several study recipients, including the emergence of resistance genotypes. IMPORTANCE This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC24). In addition, we found that current valganciclovir dosing guidelines for CMV prophylaxis are predicted to attain therapeutic targets in only 21% of recipients, which is consistent with previous pharmacokinetic studies. The novel findings of resistance mutations during subtherapeutic ganciclovir exposure presented here can inform future studies investigating the dynamics of drug selection pressure and the emergence of resistance mutations in vivo.

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Transition from antigenemia to quantitative nucleic acid amplification testing in cytomegalovirus-seropositive kidney transplant recipients receiving preemptive therapy for cytomegalovirus infection.

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