In a latest article revealed within the journal JAMA Community, researchers carried out a randomized scientific trial (RCT) to reveal the noninferiority of letermovir vs. valganciclovir for prophylaxis of cytomegalovirus (CMV) in grownup CMV-seronegative kidney transplant recipients (KTRs) who acquired a kidney from a CMV-seropositive particular person.
Examine: Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in Excessive-Danger Kidney Transplant Recipients. Picture Credit score: Hospital man / Shutterstock
Background
CMV illness is the reason for excessive mortality amongst kidney transplant recipients, and its prevalence is highest in recipients who acquired a kidney from a CMV-seropositive donor. This subgroup of CMV-seronegative KTRs includes ~20% of all KTRs. Oral valganciclovir, a CMV deoxyribonucleic acid (DNA) polymerase inhibitor, given at a every day dosage of 900mg for 200 days after transplantation, is the present care technique for CMV-seronegative KTRs.
Nonetheless, this immunosuppressant requires dose changes when kidney perform fluctuates after a kidney transplant. Additionally, it often causes leukopenia and neutropenia, which interrupts CMV prophylaxis. Furthermore, some individuals develop valganciclovir (ganciclovir)-resistant CMV after publicity to diminished concentrations of valganciclovir (ganciclovir) for a protracted period.
Letermovir, one other antiviral agent, doubtlessly overcomes all limitations of valganciclovir, like CMV-associated myelotoxicity or cross-resistance to different anti-CMV viral brokers. Extra importantly, letermovir resistance is uncommon when used as a prophylactic, even for CMV an infection in CMV-seropositive recipients of a hematopoietic stem cell transplant (HSCT). Nonetheless, it fails towards herpes simplex and varicella zoster viruses and elicits undesirable drug interactions. Thus, researchers hypothesized that letermovir could be non-inferior to valganciclovir for CMV illness prevention in KTRs.
Concerning the research
Within the current research, researchers assessed whether or not letermovir might forestall CMV illness, DNAemia, resistance, and CMV-associated leukopenia and neutropenia as a prophylactic in CMV-seronegative KTRs who acquired a kidney from a CMV-seropositive donor.
They in contrast its efficacy and security to valganciclovir on this part III, randomized, double-masked noninferiority trial, by which they masked all individuals, investigators, research workers, and sponsors to check drug administration, task, and scientific analysis. All research individuals acquired a kidney transplant inside 180 days earlier than randomization; additionally, they acquired not less than one dose of the research drug throughout main efficacy evaluation.
The group used an built-in net response system to randomize all research individuals in a 1:1 ratio to obtain research drug (letermovir) or valganciclovir, stratified primarily based on receipt of lymphocyte-depletion eliciting immunosuppression. Additionally, they assigned an identical placebo to each research medication. The first research consequence was CMV illness as much as week 52 of receiving the research drug. Within the secondary efficacy outcomes, the group assessed the incidence of CMV illness as much as week 28 and the time taken to develop CMV illness as much as week 52 if drug administration.
Additional, the group monitored opposed occasions in any respect research visits. They specified a composite security consequence encompassing an opposed occasion of neutropenia, leukopenia, white blood cell depend <3500 cells/μL, and an absolute neutrophil depend <1000 cells/μL. A further consequence was a couple of dose of granulocyte-colony stimulating issue (G-CSF) inside any 30 days throughout prophylaxis.
For each research cohorts, they assumed that the proportion of individuals with CMV illness was 0.17, and it helped them deduce that round 600 pattern dimension would obtain 90% statistical energy to reveal noninferiority of letermovir towards valganciclovir, with an total two-sided α degree equal to five%.
Thus, the highest strata of the two-sided 95% confidence interval (CI) for the share variation amongst individuals with CMV illness mustn’t exceed 10%. The group used the stratum-adjusted Mantel-Haenszel technique to compute the distinction between the 2 research teams and their two-sided 95% CI, stratified by receipt of lymphocyte-depleting immunosuppression.
Lastly, the researchers used the Miettinen and Nurminen strategies to estimate the variations within the opposed occasions throughout each teams and their 95% CIs. Moreover, they computed 95% CIs and a p-value for the inter-group variations within the proportion of individuals with a pre-outlined composite security consequence; a publish hoc evaluation estimated the time taken to elicit the composite security consequence. Moreover, they used Kaplan-Meier plots for all time-to-event analyses; and on the final evaluation, the group censored this knowledge.
Outcomes
The ultimate research evaluation set lined 586 individuals, of which 84.2% had been White and 71.6% had been males. Almost 60% of 586 research individuals acquired a kidney from a useless donor, and 46.2% additionally acquired lymphocyte depletion eliciting immunosuppression. Greater than 98% of individuals within the letermovir-receiving group and 77.4% of valganciclovir recipients confirmed not less than 90% adherence to drug use. The typical period of publicity to oral letermovir and valganciclovir was 195 and 189 days, respectively.
 Each letermovir and valganiclovir, when given for as much as 200 days after a kidney transplant, prevented CMV illness for as much as 52 weeks at comparable charges of 10.4% and 11.8%. Moreover, charges of leukopenia or neutropenia had been decrease, favoring its use for this medical situation. Moreover, they evaluated 52 individuals for CMV DNAemia and located no letermovir-resistance–related substitutions. Conversely, eight of 66 individuals within the valganciclovir group had valganciclovir resistance–associated substitutions.
The current research offers reassurance that letermovir use doesn’t elicit resistance when used as a prophylactic in CMV-seronegative KTRs who acquired a transplant from a CMV-seropositive donor. The speed of investigator-reported CMV illness was larger than committee-confirmed CMV illness, which mirrored variations in diagnostic testing in scientific observe. Nonetheless, investigator-reported CMV illness was comparable, i.e., 17.3% and 17.2% within the letermovir and valganciclovir teams.
CMV end-organ illness is presumptively handled not through invasive biopsy. Accordingly, there have been fewer individuals with committee-confirmed end-organ illness than investigator-reported CMV illness (seven vs. 61), particularly for gastrointestinal end-organ illness. The comparatively excessive price of CMV illness within the first posttransplant 12 months highlights the constraints of a 6-month common prophylaxis technique in high-risk CMV-seronegative kidney transplant recipients who obtain an organ from a CMV-seropositive donor. It additionally highlighted the constraints of a six-month prophylaxis technique used universally to forestall CMV illness in high-risk CMV-seronegative KTRs.
Conclusions
Extra individuals accomplished as much as 200 days of prophylaxis with letermovir than valganciclovir; furthermore, it had a good tolerance and security profile. Letermovir additionally induced a decrease price of quantifiable CMV DNAemia than valganciclovir throughout the prophylaxis interval (2.1% vs. 8.8%).
Decrease price of prophylaxis discontinuation attributable to an opposed occasion additional reinstated letermovir tolerability than valganciclovir (4.3% vs. 13.5%). So, whereas valganciclovir requires weight-based dose changes for intravenous administration, letermovir is dose-independent, and its dose and administration frequency stays the identical for oral and intravenous administration. In future research, researchers ought to consider whether or not prophylaxis with letermovir vs. valganciclovir interprets to diminished threat for allograft rejection and opportunistic infections.
