A Fine Balance: Using Letermovir For Salvage Antiviral Treatment While Preserving Efficacy.

D of ganciclovir-resistant or refractory cytomegalovirus (CMV) infection after transplant conveys a higher risk of morbidity and mortality and requires excellent clinical management for a positive outcome. Up to 3% of organ transplant recipients can be affected, with higher rates seen after lung transplantation. Guidelines on the management of CMV suggest foscarnet or high dose ganciclovir for management. The advent of a new commercially available antiviral agent, letermovir, a terminase inhibitor specific for CMV, adds an arrow into our therapeutic quiver. Understanding how to best use a new agent in this cohort of challenging patients remains an emerging area. For example, Turner et al described a cohort of 4 solid organ transplant recipients with ganciclovir-resistant CMV retinitis who improved on letermovir; however, three failed to maintain virologic suppression, and 2 patients developed genotypically confirmed resistance to letermovir while on therapy. In this issue of Transplantation, we have a pair of reports regarding the use of letermovir in transplant recipients with resistant or refractory CMV. Phoompoung et al describe a single-center retrospective study of 5 stem cell and organ transplant recipients who were given letermovir for the treatment of resistant or refractory CMV infection, including 3 with asymptomatic CMV viremia, one with CMV syndrome, and another with CMV pneumonitis and colitis. The 3 asymptomatic patients (with CMV viral loads at the onset of therapy ranging 637–1630 IU/mL in plasma) had a viral load decrease to <200 IU/mL with letermovir therapy; 1 was on letermovir monotherapy, another on combination therapy with foscarnet, and another with ganciclovir. A fourth patient, on combination therapy with foscarnet and letermovir, displayed a partial viral load response (2 log of viral load reduction, 45 600–910 IU/ mL after 1 mo) with a good clinical response, although developed sepsis as well as foscarnet-associated acute kidney injury and died. A fifth, who received a suboptimal dose of letermovir (240 mg IV once daily, even after cyclosporin was switched to tacrolimus), experienced an increase in viremia and subsequently died due to concomitant pneumonia and sepsis. Overall, this early work in a small and heterogenous cohort demonstrates mixed efficacy of letermovir when used alone or in various antiviral combinations in patients with resistant or refractory CMV infection. Given the lack of a control population not exposed to letermovir, along with concomitant mixed antiviral therapy in several patients, it is not clear how much impact letermovir had, or whether these patients might have cleared the viremia on their own, especially given that 3 of the 5 had very low viral loads, which are more likely to clear on their own. Veit et al report a retrospective series of 4 lung transplant recipients with resistant/refractory CMV infection in the first year after transplant who had failed both valganciclovir and foscarnet (sequentially) and were given rescue therapy with letermovir 480 mg per day (standard prophylaxis dose) for a follow up of 36.1 ± 12.9 weeks, in addition to switching to an everolimus-based immunosuppressive regimen and administration of CMV immunoglobulin. CMV viral loads at the start of therapy ranged from 2493–52 962 IU/mL in plasma. CMV decreased and was subsequently cleared after 17.7 ± 12.6 weeks. In all but 1 (the sole patient who was seropositive before transplant), letermovir was continued for many months (at significant cost), given a documented lack of CMV specific cellular immunity by enzyme-linked immune absorbent spot. Similar to the prior cohort, there was no control population not exposed to letermovir, so it is possible that some of these may have cleared with the change in immunosuppression and use of CMV immunoglobulin. A low barrier to development of resistance has been seen with letermovir. The first appearance in vitro of UL56 mutations at a median of 3 passages is earlier than the first mutations emerging under maribavir (median, 5 passages) or with foscarnet (median, 15 passages). Letermovir resistance mutations map primarily to the CMV UL56 gene at codons 231–369 and confer widely variable levels of CMV resistance. Veit et al show a relatively slow and erratic decline in CMV viral load over months in the 3 of 4 without cellular immunity to CMV. Similar results were reported in a lung transplant patient, who subsequently developed letermovir resistance. While letermovir has been shown to be effective for prophylaxis after hematopoietic stem cell transplant and is under investigation for prophylaxis after kidney transplant (ClinicalTrials. gov NCT03443869), its use as a therapeutic for resistant ISSN: 0041-1337/20/1042-240