Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients

Abstract

Letermovir, an anti-cytomegalovirus (CMV) drug, is recommended as a prophylactic agent in patients at risk of CMV infection/reactivation after allogeneic hematopoietic stem cell transplant. We report the curative and pre-emptive use of letermovir in two heart transplant recipients. In one patient with ganciclovir-resistant CMV, letermovir was successfully used to treat CMV colitis. In the second patient, letermovir was used as pre-emptive therapy for CMV reactivation, but did not prevent CMV esophagitis. In both cases, letermovir was successful for secondary prophylaxis. Curative use of letermovir may be considered if resistance or major adverse effect of other antivirals therapy is suspected.

Letermovir is a new well-tolerated treatment of cytomegalovirus (CMV) infection that targets the viral terminase, contrary to previously available antivirals targeting the viral DNA polymerase (UL54) and that display myelotoxicity ((val)ganciclovir) or nephrotoxicity (foscarnet and (brin)cidofovir).^1,2,3 It is recommended as a prophylactic agent in patients at high risk of CMV infection/reactivation after an allogeneic hematopoietic stem cell transplant (HSCT). Here, we report the use of letermovir as a pre-emptive and/or curative treatment for CMV reactivation and/or disease in two heart transplant recipients.

Cases

The first patient, a 50-year-old female, received a heart transplantation on January 31st 2019 because of severe idiopathic dilated cardiomyopathy. The donor was seropositive for CMV, whereas she was seronegative (D+/R-). She received preventive valganciclovir (900 mg per day) for 6 months. Four months after prophylaxis discontinuation, the systematic monitoring of CMV-DNAemia detected 384,500 copies/mL viremia, without any symptoms (Figure 1). The patient received IV ganciclovir (5 mg/kg/12 h) for 2 weeks followed by valganciclovir (900 mg bid) for 3 weeks, leading to undetectable CMV-DNAemia. As the patient had no history of cardiac rejection, immunosuppression could be decreased (cortico-steroid and calcineurin-inhibitor). While on secondary prophylaxis with valganciclovir (900 mg per day), CMV-DNAemia was again positive at 8920 copies/mL, concomitantly with severe neutropenia (PNN at 0.9 G/L) and diarrhea. Valganciclovir was increased to a curative dose (900 mg bid) through G-CSF injections. CMV-DNAemia decreased, although the patient was readmitted for severe renal failure related to diarrhea and dehydration. In sigmoid biopsy, CMV load on tissue was 66 copies/µg of DNA in favor of CMV disease, and norovirus was detected. At that time, blood CMV-DNAemia was 4782 copies/mL and CMV was proven resistant to ganciclovir/valganciclovir with a high-level resistance mutation in UL97 (A594V). Valganciclovir was replaced by letermovir at 480 mg per day for 3.5 months. CMV-DNAemia became undetectable 3 weeks later and remained negative during the 2-years follow-up.

Figure 1.

Time line representing CMV viral loads, immunosuppressive drugs, antiviral drugs and clinical events of case 1. The small graph in the large one represents a zoom of the part marked by the dotted lines. VGC = Valganciclovir.

The second patient, a 55-year-old female, received a heart transplantation on 9 April 2020 because of a dilated post-partum myocardiopathy (diagnosed 20 years earlier). She had chronic kidney failure (creatinine clearance 30 mL/min). Both donor and recipient were seropositive for CMV (D+/R+), so the patient received preventive valganciclovir (450 mg twice a week, adapted to renal function). Due to CMV-DNAemia at 1339 copies/mL, valganciclovir was increased (450 mg bid), leading to undetectable CMV-DNAemia (Figure 2). Severe neutropenia and thrombocytopenia then occurred, and valganciclovir was discontinued after 8 weeks, leading to the correction of both cytopenia. After 3 weeks, CMV-DNAemia was 2130 copies/mL without symptoms. Immunosuppression was decreased (cortico-steroid and calcineurin-inhibitor), without incidence on rejection. Because of previous (val)ganciclovir hematotoxicity, and the high risk of further kidney failure associated with foscarnet, letermovir was introduced (480 mg/day) as pre-emptive treatment. After 16 days, the patient presented CMV esophagitis, proven by CMV immunostaining in biopsies, while CMV-DNAemia remained negative. Letermovir was replaced by IV ganciclovir (2.5 mg/kg/24 h) for 3 weeks, and esophagitis regressed. Ganciclovir was again replaced by letermovir for a period of 6 weeks. One year later, there was no CMV reactivation.

Figure 2.

Time line representing CMV viral loads, immunosuppressive, antiviral drugs and clinical events of case 2. VGC = Valganciclovir; ARF = Adapted to the renal function.

Discussions

Cytomegalovirus infection is one of the most significant complications in HSCT and solid organ transplantation (SOT) recipients and is associated with increased morbidity and poor long-term survival. ⁴ (Val)ganciclovir is the first line of treatment for CMV but is associated with myelosuppression. Foscarnet and cidofovir, as the second lines of treatment, are associated with nephrotoxicity and hypokalemia. ¹ (Val)ganciclovir is widely used in post-transplant prophylaxis for high-risk recipients and has shown a significant reduction in the risk of CMV disease and all-cause mortality. ⁵ Maribavir is now also available for the treatment of resistant/refractory CMV infections but was not used routinely in our center.

In 2017, the Food and Drug Administration and European Medicines Agency approved the use of letermovir for the prophylaxis of CMV infection and disease in CMV-seropositive HSCT recipients, ² which has proven to be a major advance. Letermovir inhibits human CMV replication by binding to the terminase complex (UL56, UL 89, and UL51) and inhibiting the packaging of CMV progeny DNA into capsids, thus resulting in non-infectious long DNA particles.^1,3 Other HSCT cohorts showed that letermovir can be useful when used as secondary prophylaxis. ⁶ However, there are no solid data to support the use of letermovir as curative therapy after HSCT, and letermovir is not approved for any indications in SOT. We report here cases of pre-emptive and curative treatment with letermovir in two heart transplant recipients, followed by secondary prophylaxis.

In both cases, letermovir was successfully used as secondary prophylaxis (for 3.5 months in the first case and 2 months in the second), as already described in SOT recipients^7,8 and contrary to the findings of Aryal ⁹ (Table 1). Duration of secondary prophylaxis with letermovir was modeled on what is usually recommended for secondary prophylaxis with valganciclovir in heart transplantation. It should be noted that Winstead reported the successful use of letermovir in primary prophylaxis in SOT recipients ¹⁰ (Table 1).

Table 1.

Reported of use of Letermovir in solid organ transplantation SOT.

Reference/Year of publication	Organ graft	Situation	Reason	Letermovir use (dose)	Issue
Koepf/(2020) (7)	1 kidney TR	CMV disease	CMV resistance	Secondary prophylaxis (480 mg/day)	Favorable
Chong/(2018) (8)	1 heart TR	CMV viremia and syndrome	CMV resistance or foscarnet nephrotoxicity and cidofovir uveitis	Secondary prophylaxis (480 mg/day/3 months)	Favorable
Aryal/(2019) (9)	8 lung TR and heart TR	8 CMV prophylaxis	(Val)ganciclovir-associated leukopenia or CMV resistance	2 Primary prophylaxis	3/8 prophylaxis failure (CMV-DNAeamia)
		2 CMV-DNAeamia		6 secondary prophylaxis (480 mg/day)
				2 pre-emptive treatments	1/2 pre-emptive failure
Winstead/(2021) (10)	31 TR	CMV prophylaxis	Severe leukopenia	Primary prophylaxis (480 mg/day)	Favorable
Linder/(2021) (11)	27 SOT (2 heart TR)	CMV disease	CMV resistance (32%) clinically refractory (13%) intolerance to other treatment (77%)	480 mg/day (87%)	Favorable when CMV-DNAemia was < 1000 IU/ml at letermovir initiation
				720 mg/day (13%)	50% worsening of symptoms when CMV-DNAemia was > 1000 IU/ml at letermovir initiation for end organ disease
Tumer/(2019) (12)	2 lung TR and 2 heart TR	CMV syndrome Retinitis	CMV resistance or foscarnet nephrotoxicity	Curative treatment (720 mg/day)	3 letermovir resistance (UL56 mutation)
Cherrier/(2018) (13)	1 lung TR	CMV viremia	CMV resistant	Curative treatment (480 mg/day)	1 letermovir resistance (UL56 mutation)

CMV = cytomegalovirus; TR = transplant recipient.

In our first case, letermovir was used with success as curative strategy because of CMV ganciclovir-resistance, renal insufficiency, and neutropenia. Only few reports have been published on the favorable use of letermovir as a curative treatment in heart transplantation. Linder conducted an observational study to determine the patterns of use and outcome of letermovir treatment of CMV infection on 27 transplant recipients (7% were heart transplant recipients). End organ disease was present on 36%, with the gastrointestinal tract as the most common involved site (76%). Patients treated with letermovir with viral load< 1000 IU/mL had good virologic outcomes. Outcomes were mixed when letermovir was initiated at higher viral loads. ¹¹

In the second case, pre-emptive letermovir failed, since CMV esophagitis occurred. One study previously reported the failure of curative letermovir in SOT recipients for CMV retinitis, ¹² while two others described the failure of pre-emptive letermovir^9,13 (Table 1). One could suggest a poor absorption of letermovir in the setting of CMV gastrointestinal disease, but the undetectable CMV-DNA in the blood does not support this hypothesis. Another explanation could be a poor tissue penetration of letermovir. In preclinical distribution studies on volunteers, letermovir is well distributed with the highest concentrations in the gastrointestinal tract. ¹⁴ However, our second clinical case raises question on curative use of letermovir in gastrointestinal disorder because no scientific or medical publication exists on this topic in humans.

The mutations associated with letermovir resistance are most commonly mapped on UL56 (>UL89>UL51). ¹³ The low genetic barrier of letermovir cautions against its use during infections with high-level replications. In our cases, we did not evaluate letermovir resistance because of the success of letermovir secondary prophylaxis.

Letermovir is well tolerated, although it is an inducer of cytochrome P450 3A as well as an inhibitor of cytochrome 2C8; it also increases the exposure to calcineurin inhibitors. ¹⁵ The catabolism of letermovir is reduced when co-administrated with cyclosporine (but not tacrolimus), ¹⁵ with a bidirectional interaction that requires a dose reduction of letermovir from 480 to 240 mg once daily. Nevertheless, Winstead reported the significant drug interaction between letermovir and tacrolimus, leading to a 40–50% reduction in the dose of tacrolimus upon the initiation of letermovir. ¹⁰ In our cases, tacrolimus was monitored weekly and tacrolimus was decreased by 30–40% while on letermovir therapy.

In conclusion, letermovir could be used off-label, with efficacy, as preventive therapy in heart transplantation, especially when side effects or resistance prevent use of first-line treatment. It should be used with caution as curative treatment, since letermovir was used as curative therapy in low-level CMV-DNAemia in our 2 cases. Trials are needed in heart transplantation to discuss its use in clinical practice.