New Antiviral Option for CMV Prophylaxis After Kidney Transplant

In a clinical trial of cytomegalovirus (CMV) prophylaxis in high-risk kidney transplant patients, letermovir (previmis) proved to be no inferior to standard of care valganciclovir (valcite), researchers reported .

and Phase III trial When 589 patients were randomized 1:1 to receive either drug for 200 days after transplantation, CMV incidence at 1 year was not significantly different between the letermovir and valganciclovir groups (10.4 % vs 11.8%, adjusted difference -1.4%, 95% CI -6.5% to 3.8%), reported Ajit Limaye, M.D., Washington Medical College, Seattle and colleagues.

Rates of myelosuppression (leukopenia or neutropenia) at 28 weeks were significantly lower with letermovir compared with valganciclovir (26% vs. 64%, P.<0.001), researchers reported: JAMA.

In addition, compared with the valganciclovir group, fewer participants in the letermovir group discontinued prophylaxis due to adverse events (4.1% vs. 13.5%) or drug-related adverse events (2.7% vs. 8.8%), the researchers said. .

“Cytomegalovirus disease is the leading cause of morbidity and mortality in kidney transplant recipients,” write Limaye et al. “The incidence is highest in the subgroup of CMV-seronegative renal transplant recipients whose organs are transplanted from CMV-seropositive donors, accounting for approximately 20% of all renal transplant recipients.”

However, researchers noted that the standard prophylaxis valganciclovir has important limitations. Dose adjustments are required and patients are known to develop tolerance. In addition, valganciclovir generally causes myelosuppression, especially leukopenia and neutropenia, which may require immunosuppressant discontinuation or dose reduction.

“Retermovir is a non-myelotoxic, active antiviral agent against CMV, does not require dose adjustment for renal damage, has a unique mechanism of action as an inhibitor of the CMV DNA It is not associated with cross-resistance to anti-CMV agents,” the study authors said.

However, letermovir has its own limitations, Limaye et al. Unlike valganciclovir, it has no activity against herpes simplex virus (HSV) or varicella-zoster virus (VZV). It may also interact with other drugs as a moderate cytochrome P3450 3A inhibitor.

Letermovir was approved by the FDA in 2017 for CMV prophylaxis in CMV-seropositive adult hematopoietic cell transplant recipients and has been widely adopted in this population. Merck, the manufacturer of this drug, announced today Based on the results of the current study, the FDA also announced approval of letermovir for CMV prophylaxis in high-risk adult kidney transplant recipients.

and Editor Zoe Raglow, M.D., and Daniel R. Kaul, M.D., of the University of Michigan School of Medicine in Ann Arbor, who accompanied the study, said another limitation of Letermobil is its cost. “The average daily cost of letermovir (about $250 per day) is more than 20 times higher than generic valganciclovir, making it one of the most expensive post-transplant regular treatments, so cost is a factor. It certainly will,” the researchers wrote.

Nonetheless, Laglou and Kaur said the results presented by Limae’s group were “game-changing” and that clinicians should consider rethermobil primarily in consideration of patients likely to benefit. He said it is necessary to weigh the limitations and advantages of “Letermovir may be most cost-effective when used in patients with baseline leukopenia or those who develop leukopenia during valganciclovir treatment,” the editors suggested.

A double-blind, double-dummy phase III trial included the highest-risk adult patients: CMV-seronegative renal transplant recipients who received organs from CMV-seropositive donors. The majority were white (84%) and male (71%).

The letermovir group received letermovir 480 mg orally daily, acyclovir 400 mg twice daily (for HSV and VZV prophylaxis), and valganciclovir placebo. The valganciclovir group received valganciclovir 900 mg orally daily along with letermovir and acyclovir placebo. The researchers noted that acyclovir had no activity against CMV.

The primary outcome was CMV disease, with a prespecified non-inferiority difference of 10%, ascertained by an independent masked adjudication committee up to 52 weeks after transplantation. The rate of leukopenia or neutropenia by week 28 was a prespecified safety outcome.

Secondary outcomes included CMV disease by 28 weeks and time to onset of CMV disease. By week 28, he had no participants in the letermovir group who developed CMV disease, compared to five participants in the valganciclovir group. Time to onset of CMV disease was similar between groups (HR 0.90, 95% CI 0.56-1.47).

The research team said that bone marrow toxicity is assessed as leukopenia or neutropenia, but that valganciclovir can cause anemia and thrombocytopenia, among other limitations of the study. Cost analysis was also not performed, although cost was an important consideration for Letermovir.

Furthermore, the study lacked diversity, even though the risk of CMV disease was not related to gender, race, or ethnicity, the authors said. Finally, the long-term outcome of CMV disease has not been formally evaluated. “However, because CMV disease was comparable between groups, there is no reason to expect a difference in long-term outcomes between letermovir and valganciclovir,” the researchers said.