Development 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.1 Up to 3% of organ transplant recipients can be affected, with higher rates seen after lung transplantation.2 Guidelines on the management of CMV suggest foscarnet or high dose ganciclovir for management.1,2 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 al3 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 al4 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 al5 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).6 Letermovir resistance mutations map primarily to the CMV UL56 gene at codons 231–369 and confer widely variable levels of CMV resistance.6 Veit et al5 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.7 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 or refractory CMV may be limited, especially with high viral loads. Given the advent of other effective options for treatment of CMV, we may wish to preserve letermovir for prophylaxis.
Transplant clinicians should be aware of the significant drug interactions with letermovir. Veit et al5 report that a small adjustment of the tacrolimus dose was indicated with letermovir treatment. The package insert recommends a dose reduction when used with cyclosporin, and other interactions such as with tacrolimus, sirolimus, and voriconazole are significant, necessitating therapeutic drug monitoring.8 Failure to increase the dose of letermovir after cessation of cyclosporin in the report by Phoompoung et al4 may have resulted in treatment failure. Furthermore, the optimal dosing for treatment has not been studied, and use of prophylaxis dosing may be enhancing the development of resistance.
As more antivirals with activity against CMV become available, combination therapy may become a reality. Not all combinations are positive; for example, maribavir has been shown to have additive interactions with foscarnet, cidofovir, and letermovir when tested against wild type and mutant viruses, strong synergy with rapamycin, yet strong antagonism with ganciclovir.9 Letermovir has been shown to be synergistic with ganciclovir, foscarnet, (brin)cidofovir, maribavir, and other experimental agents.10 With the DNA polymerase inhibitors such as ganciclovir, foscarnet, and cidofovir, early chain termination due to incorporation of the nucleoside analogue into replicating viral DNA results in a reduction of concatemeric viral DNA and a reduction in CMV-encoded late proteins, which may enhance the efficacy of the terminase inhibitors (ie, letermovir) since there is less functional enzyme that needs to be inhibited.10 We do not yet have clinical data, and from these 2 cohorts, we are not able to draw significant conclusions, although in vitro work would be supportive of drug combinations. We are now privileged to have access to multiple novel antivirals against CMV and need to be sure we use them in as optimal a fashion as possible, balancing risk of further resistance, cost, and toxicities.
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4. Phoompoung P, Ferreira VH, Tikkanen J, et al. Letermovir as salvage therapy for CMV infection in transplant recipients.Transplantation2020104404–409
5. Veit T, Munker D, Kauke T, et al. Letermovir for difficult to treat cytomegalovirus infection in lung transplant recipients.Transplantation2020104410–414
6. Chou S. Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance.Antimicrob Agents Chemother2015596588–6593
7. Cherrier L, Nasar A, Goodlet KJ, et al. Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection.Am J Transplant2018183060–3064
8. Kotton CN. Updates on antiviral drugs for cytomegalovirus prevention and treatment.Curr Opin Organ Transplant201924469–475
9. Chou S, Ercolani RJ, Derakhchan K. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus.Antiviral Res2018157128–133
10. O’Brien MS, Markovich KC, Selleseth D, et al. In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus.Antiviral Res2018158255–263