In a recent article published in the journal JAMA Network, researchers performed a randomized clinical trial (RCT) to demonstrate the noninferiority of letermovir vs. valganciclovir for prophylaxis of cytomegalovirus (CMV) in adult CMV-seronegative kidney transplant recipients (KTRs) who received a kidney from a CMV-seropositive individual.
Study: Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients. Image Credit: Hospital man / Shutterstock
Background
CMV disease is the cause of high mortality among kidney transplant recipients, and its prevalence is highest in recipients who received a kidney from a CMV-seropositive donor. This subgroup of CMV-seronegative KTRs comprises ~20% of all KTRs. Oral valganciclovir, a CMV deoxyribonucleic acid (DNA) polymerase inhibitor, given at a daily dosage of 900mg for 200 days after transplantation, is the current care strategy for CMV-seronegative KTRs.
However, this immunosuppressant requires dose adjustments when kidney function fluctuates after a kidney transplant. Also, it frequently causes leukopenia and neutropenia, which interrupts CMV prophylaxis. Moreover, some people develop valganciclovir (ganciclovir)-resistant CMV after exposure to reduced concentrations of valganciclovir (ganciclovir) for a long duration.
Letermovir, another antiviral agent, potentially overcomes all limitations of valganciclovir, like CMV-associated myelotoxicity or cross-resistance to other anti-CMV viral agents. More importantly, letermovir resistance is rare when used as a prophylactic, even for CMV infection in CMV-seropositive recipients of a hematopoietic stem cell transplant (HSCT). However, it fails against herpes simplex and varicella zoster viruses and elicits unwanted drug interactions. Thus, researchers hypothesized that letermovir would be non-inferior to valganciclovir for CMV disease prevention in KTRs.
About the study
In the present study, researchers assessed whether letermovir could prevent CMV disease, DNAemia, resistance, and CMV-associated leukopenia and neutropenia as a prophylactic in CMV-seronegative KTRs who received a kidney from a CMV-seropositive donor.
They compared its efficacy and safety to valganciclovir in this phase III, randomized, double-masked noninferiority trial, in which they masked all participants, investigators, study staff, and sponsors to study drug administration, assignment, and clinical evaluation. All study participants received a kidney transplant within 180 days before randomization; also, they received at least one dose of the study drug during primary efficacy analysis.
The team used an integrated web response system to randomize all study participants in a 1:1 ratio to receive study drug (letermovir) or valganciclovir, stratified based on receipt of lymphocyte-depletion eliciting immunosuppression. Also, they assigned a matching placebo to both study drugs. The primary study outcome was CMV disease up to week 52 of receiving the study drug. In the secondary efficacy outcomes, the team assessed the incidence of CMV disease up to week 28 and the time taken to develop CMV disease up to week 52 if drug administration.
Further, the team monitored adverse events at all study visits. They specified a composite safety outcome encompassing an adverse event of neutropenia, leukopenia, white blood cell count <3500 cells/μL, and an absolute neutrophil count <1000 cells/μL. An additional outcome was more than one dose of granulocyte-colony stimulating factor (G-CSF) within any 30 days during prophylaxis.
For both study cohorts, they assumed that the proportion of participants with CMV disease was 0.17, and it helped them deduce that around 600 sample size would achieve 90% statistical power to demonstrate noninferiority of letermovir against valganciclovir, with an overall two-sided α level equal to 5%.
Thus, the top strata of the two-sided 95% confidence interval (CI) for the percentage variation among participants with CMV disease should not exceed 10%. The team used the stratum-adjusted Mantel-Haenszel method to compute the difference between the two study groups and their two-sided 95% CI, stratified by receipt of lymphocyte-depleting immunosuppression.
Finally, the researchers used the Miettinen and Nurminen methods to estimate the variations in the adverse events across both groups and their 95% CIs. Additionally, they computed 95% CIs and a p-value for the inter-group variations in the proportion of participants with a pre-outlined composite safety outcome; a post hoc analysis estimated the time taken to elicit the composite safety outcome. Furthermore, they used Kaplan-Meier plots for all time-to-event analyses; and at the last assessment, the team censored this data.
Results
The final study analysis set covered 586 participants, of which 84.2% were White and 71.6% were men. Nearly 60% of 586 study participants received a kidney from a dead donor, and 46.2% also received lymphocyte depletion eliciting immunosuppression. More than 98% of participants in the letermovir-receiving group and 77.4% of valganciclovir recipients showed at least 90% adherence to drug use. The average duration of exposure to oral letermovir and valganciclovir was 195 and 189 days, respectively.
Both letermovir and valganiclovir, when given for up to 200 days after a kidney transplant, prevented CMV disease for up to 52 weeks at comparable rates of 10.4% and 11.8%. Additionally, rates of leukopenia or neutropenia were lower, favoring its use for this medical condition. Furthermore, they evaluated 52 participants for CMV DNAemia and found no letermovir-resistance–associated substitutions. Conversely, eight of 66 participants in the valganciclovir group had valganciclovir resistance–related substitutions.
The present study provides reassurance that letermovir use does not elicit resistance when used as a prophylactic in CMV-seronegative KTRs who received a transplant from a CMV-seropositive donor. The rate of investigator-reported CMV disease was higher than committee-confirmed CMV disease, which reflected differences in diagnostic testing in clinical practice. However, investigator-reported CMV disease was comparable, i.e., 17.3% and 17.2% in the letermovir and valganciclovir groups.
CMV end-organ disease is presumptively treated not via invasive biopsy. Accordingly, there were fewer participants with committee-confirmed end-organ disease than investigator-reported CMV disease (seven vs. 61), especially for gastrointestinal end-organ disease. The relatively high rate of CMV disease in the first posttransplant year highlights the limitations of a 6-month universal prophylaxis strategy in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. It also highlighted the limitations of a six-month prophylaxis strategy used universally to prevent CMV disease in high-risk CMV-seronegative KTRs.
Conclusions
More participants completed up to 200 days of prophylaxis with letermovir than valganciclovir; moreover, it had a favorable tolerance and safety profile. Letermovir also induced a lower rate of quantifiable CMV DNAemia than valganciclovir during the prophylaxis period (2.1% vs. 8.8%).
Lower rate of prophylaxis discontinuation due to an adverse event further reinstated letermovir tolerability than valganciclovir (4.3% vs. 13.5%). So, while valganciclovir requires weight-based dose adjustments for intravenous administration, letermovir is dose-independent, and its dose and administration frequency remains the same for oral and intravenous administration. In future studies, researchers should evaluate whether prophylaxis with letermovir vs. valganciclovir translates to reduced risk for allograft rejection and opportunistic infections.
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