Cytomegalovirus Prevention in Thoracic Organ Transplantation: A Single-Center Evaluation of Letermovir Prophylaxis

Abstract

Background:

Cytomegalovirus (CMV) infection is common following thoracic organ transplantation and causes substantial morbidity and mortality. Letermovir is a novel antiviral agent used off-label in this population for CMV prevention. Our goal was to understand patterns of letermovir use and effectiveness when applied for CMV prophylaxis after thoracic transplantation.

Methods:

We retrospectively evaluated letermovir use among thoracic transplant recipients at an academic transplant center who initiated letermovir from 1/2018 – 10/2019 for CMV prophylaxis. We analyzed indication, timing, and duration of prophylaxis; tolerability; and occurrence of breakthrough CMV DNAemia and disease.

Results:

Forty-two episodes of letermovir prophylaxis occurred in 41 patients, including 37 lung and 4 heart transplant recipients. Primary prophylaxis (26/42, 61.9%) was utilized mainly due to myelosuppression (25/26, 96.2%) and was initiated a median of 315 days post-transplant (interquartile range [IQR] 125–1139 days). Sixteen episodes of secondary prophylaxis (16/42, 38.1%) were initiated a median of 695 days post-transplant (IQR 537–1156 days) due to myelosuppression (10/16, 62.5%) or prior CMV resistance (6/16, 37.5%). Median duration of letermovir prophylaxis was 282 days (IQR 131–433 days). Adverse effects required letermovir cessation in 5/42 (11.9%) episodes. Only one episode (2.4%) was complicated by clinically significant breakthrough CMV infection. Transient low-level CMV DNAemia (< 450 IU/mL) occurred in 15 episodes (35.7%) but did not require letermovir cessation.

Conclusions:

Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort of thoracic transplant recipients. Further prospective trials of letermovir prophylaxis in this population are warranted.

Introduction

Thoracic organ transplantation is a life-saving intervention for individuals with end-stage lung or heart disease. However, the intense immunosuppressive regimens applied result in susceptibility to infectious pathogens including cytomegalovirus (CMV). CMV is a member of the Herpesviridae family of viruses and is among the most common viral pathogens in the transplant population. It is associated with significant morbidity and mortality through both its direct (e.g., CMV syndrome and end-organ disease) and indirect effects (e.g., allograft dysfunction and susceptibility to opportunistic infections).[1, 2]

The pursuit for effective CMV preventative strategies in transplantation includes novel antivirals, vaccines, and immunologic monitoring tools. Effective antivirals for CMV prevention are paramount, but use of commonly prescribed agents, such as valganciclovir and ganciclovir, can be complicated by intolerance, including myelosuppression, and development of antiviral resistance.[2, 3] Also, controversy exists regarding the optimal duration of CMV prophylaxis, particularly for patients at high risk for CMV disease, such as CMV mismatched (e.g., donor CMV seropositive [D+], recipient CMV seronegative [R-]) lung transplant recipients. Transplant clinicians must balance the potential for adverse effects, resistance emergence, and high drug cost against the development of delayed-onset CMV disease following prophylaxis cessation.[2–6]

Letermovir is a novel anti-CMV therapy targeting the viral terminase complex, a site involved late in the viral replication process. This site is separate from targets of other currently used anti-CMV therapies, and as a result, letermovir typically lacks issues of cross-resistance and toxicities seen with other agents, such as valganciclovir and ganciclovir.[7] Letermovir is highly bioavailable and can be administrated via both the oral and intravenous route.[8] In addition, letermovir is approved by the Food and Drug Administration for primary CMV prevention in CMV-seropositive adult allogeneic hematopoietic cell transplant recipients based on a randomized clinical trial demonstrating reduced clinically significant CMV infection through 24 weeks post-transplant.[9] However, letermovir has been increasingly utilized off-label for CMV prevention in the thoracic organ transplant population with mixed results.[10–12]

The primary objective of this study was to analyze a large transplant center’s experience with letermovir for primary and secondary CMV prophylaxis in thoracic organ transplant recipients, including the timeline, tolerability, and outcomes associated with letermovir use.

Materials and Methods

Study Design and Study Center

This single-center retrospective study analyzed clinical characteristics and outcomes of patients with a history of thoracic organ transplantation (heart, lung or any combined solid organ transplant [SOT] including heart or lung transplant) who received care at Duke University Hospital (DUH) and associated clinics. The study cohort included all thoracic organ transplant patients who initiated letermovir for primary or secondary CMV prophylaxis between January 1, 2018 and October 31, 2019 and were followed by the DUH transplant teams while on letermovir prophylaxis. Clinical follow-up data were analyzed through May 15, 2020, at least 6 months after letermovir initiation for all patients.

DUH is a 957 bed academic transplant hospital in central North Carolina. During the study period, DUH CMV prophylaxis protocols were based on donor and recipient CMV serostatus and the organ transplanted. Primary CMV prophylaxis was applied based upon risk stratification in patients without a history of CMV infection or disease. High risk (e.g., CMV D+, CMV R-) lung and heart-lung transplant recipients received indefinite primary CMV antiviral prophylaxis with intravenous ganciclovir early post-transplant followed by transition to oral valganciclovir once oral therapies were tolerated, whereas high risk heart transplant recipients continued CMV prophylaxis with valganciclovir for 6 months following transplant. Intermediate risk (e.g., CMV D+/−, CMV R+) lung and heart-lung transplant recipients continued valganciclovir for at least one year post-transplant. Intermediate risk heart transplant recipients received either 3 months of valganciclovir prophylaxis or underwent pre-emptive CMV monitoring with weekly quantitative plasma CMV polymerase chain reaction (PCR) testing while receiving acyclovir or valacyclovir. Finally, low risk patients (CMV D-, CMV R-) received acyclovir or valacyclovir for viral prophylaxis for at least 3 months. Secondary CMV prophylaxis, the use of prophylactic doses of antiviral therapy at a point after completion of treatment doses for CMV DNAemia or disease, was continued for a minimum of 3 months in all groups except CMV high risk lung and heart-lung transplant recipients who continued secondary prophylaxis indefinitely if feasible. The off-label use of letermovir prophylaxis was limited to those with either resistance or intolerance to standard CMV prophylactic regimens.

Quantitative plasma CMV PCR testing was performed at DUH utilizing the COBAS^® AmpliPrep/COBAS^® TaqMan^® CMV Test (Roche, Indianapolis, IN) for amplification and detection of a specific region of the CMV genome with a lower limit of quantification of 137 IU/mL. Plasma CMV PCR testing may also have been performed in laboratories external to DUH based on patients’ distance from DUH and time interval post-transplant. External CMV PCR values were recorded in patients’ electronic medical records.

The primary immunosuppression regimen for this cohort included induction therapy with basiliximab followed by maintenance therapy with a calcineurin inhibitor (e.g., tacrolimus or cyclosporine), an antimetabolite (e.g., mycophenolate mofetil or azathioprine), and steroids. When myelosuppression occurred, the antimetabolite dose was often decreased, or the antimetabolite was temporarily discontinued.

Data Extraction and Statistical Analysis

Pharmacy records were utilized to generate the cohort of thoracic organ transplant patients who received letermovir during the study period. Clinical data analyzed included baseline demographics (e.g., age, gender, ethnicity, transplant type, underlying disease, and CMV serostatus), immunosuppression, and rejection episodes prior to letermovir use. Letermovir-specific variables collected included the date of initiation, dose, duration of prophylaxis, and rationale for use, as well as toxicities and clinical outcomes experienced while on letermovir, including breakthrough CMV DNAemia and disease. Hematologic parameters (e.g., white blood cells [WBCs], hemoglobin, and platelets) were recorded during letermovir therapy. These variables were extracted from the DUH electronic medical record by manual chart review and entered into a secure database. Continuous data were reported as medians with the stated range or interquartile range (IQR), and summary descriptive statistics were applied. Comparisons of hematologic parameters at the beginning and end of letermovir prophylaxis were performed with Wilcoxon signed-rank tests; p < 0.05 was considered statistically significant. Analyses were performed in SAS software, version 9.4 (SAS Institute, Cary, North Carolina, USA). The study was approved by the Duke University Health System Institutional Review Board.

Definitions:

Accepted clinical trial definitions for CMV infection and disease in transplant recipients were utilized.[13] CMV viral resistance was determined via a CMV genotype demonstrating the presence of a UL97, UL54, or UL56 mutation, confirmed in previous studies to confer antiviral resistance through marker transfer experiments.[14, 15] Resistance testing was performed externally by Eurofins Viracor (Lee’s Summit, MO, USA), and assessment for UL56 mutations was available from May 2018 onward. A formal protocol guiding institutional use of letermovir prophylaxis and associated laboratory monitoring did not exist during the study period. A plasma CMV PCR value of ≥ 450 IU/mL was the defined threshold for initiation of CMV therapy (e.g., valganciclovir, ganciclovir, and foscarnet) when utilizing a pre-emptive strategy for prophylaxis in this population. Clinically significant breakthrough CMV infection during letermovir prophylaxis was defined as CMV DNAemia or disease resulting in a change from letermovir prophylaxis to treatment doses of an alternate anti-CMV therapy. Letermovir adverse effects resulting in cessation of letermovir prophylaxis were recorded. Successful completion of letermovir prophylaxis was defined as completion of the planned course of letermovir prophylaxis without complications (e.g., toxicities, clinically significant breakthrough CMV infection) necessitating early cessation. Immunosuppressive therapy recorded included maintenance therapy at the time of letermovir initiation with the steroid dose reflecting the highest dose administered in the preceding month before letermovir initiation. Additionally, the use of augmented immunosuppression for rejection was recorded, including high dose steroids or anti-thymocyte globulin (ATG) in the preceding 6 months before letermovir initiation, or alemtuzumab in the preceding 12 months.

Results:

Forty-two episodes of letermovir prophylaxis occurred in 41 thoracic organ transplant recipients including 36 lungs, 4 hearts, and 1 combined liver-lung transplant recipient (Table 1). Six recipients (14.6%) had undergone redo bilateral orthotopic lung transplantation. Primary prophylaxis with letermovir was most common (26/42 episodes, 61.9%) and was utilized solely in lung transplant recipients, whereas secondary letermovir prophylaxis (16/42 episodes, 38.1%) was applied in both lung (12/16, 75%) and heart transplant (4/16, 25%) recipients. One patient received letermovir for primary prophylaxis following their second and third lung transplant, and both episodes were included in the analysis.

Table 1.

Baseline Patient Characteristics

Characteristic	N=41a
Age in years, median (range)	53 (23–76)
Male, no. (%)	25 (61)
Race, no. (%)
White/Caucasian	38 (92.7)
Black or African American	2 (4.9)
Asian Indian	1 (2.4)
Ethnicity (Non-Hispanic), no. (%)	41 (100)
Transplant Type, no. (%)
Lung	37 (90.2)
SOLT	5 (12.2)
BOLTb	32 (78)
Heart	4 (9.8)
Prior solid organ transplant, no. (%)c	6 (14.6)
Underlying disease
Idiopathic pulmonary fibrosis	14 (34.1)
Cystic fibrosis	12 (29.3)
Chronic obstructive pulmonary disease/emphysema	5 (12.2)
Brochiolitis obliteransd	2 (4.9)
Characteristic	N=41 a
Non-ischemic cardiomyopathy	2 (4.9)
Othere	6 (14.6)
CMV Serostatus, no. (%)f
Donor positive, recipient negative	21 (51.2)
Donor positive, recipient positive	10 (24.4)
Donor negative, recipient positive	8 (19.5)
Donor negative, recipient negative	1 (2.4)

BOLT: bilateral orthotopic lung transplant, CMV: cytomegalovirus; SOLT: single orthotopic lung transplant.

^aOne patient received letermovir twice and the first episode represented in Table 1.

^bOne patient received a combined liver-lung transplant.

^cAll re-transplant patients had undergone prior bilateral orthotopic lung transplantation.

^dOccurrence following allogeneic hematopoietic cell transplantation.

^eOther underlying diseases include: alpha-1-antitrypsin deficiency (n=1), hypersensitivity pneumonitis (n=1), ischemic cardiomyopathy (n=1), non-specific interstitial pneumonitis (n=1), primary ciliary dyskinesia (n=1), and restrictive cardiomyopathy (n=1).

^fOne patient with unknown donor CMV serostatus (recipient CMV seropositive).

At the time of letermovir initiation, patients were receiving a median of 2 (range 2–4) immunosuppressive agents (Table 2). Immunosuppressive therapies included steroids (42/42, 100%), tacrolimus (31/42, 73.8%), cyclosporine (10/42, 23.8%), mycophenolate (11/42, 26.2%), azathioprine (3/42, 7.1%), and belatacept (1/42, 2.4%). In addition, receipt of augmented immunosuppressive therapy for rejection, including high dose steroids or ATG within 6 months, or alemtuzumab within 12 months, prior to letermovir initiation occurred in nearly half (19/42, 45.2%) of letermovir prophylaxis episodes. Among the 28/42 (66.7%) episodes in which patients were off their antimetabolite at letermovir initiation, 17/28 (60.7%) resumed an antimetabolite at some point between letermovir initiation and cessation. The most common letermovir dose used in both groups was 480mg daily, which is the standard dosing for patients on tacrolimus, the primary calcineurin inhibitor utilized in the cohort. Two patients received secondary prophylaxis at a dose of 720mg daily given perceived high risk for breakthrough CMV infection.

Table 2.

Immunosuppressive Therapy Associated with Letermovir Episodes (N=42)

Immunosuppressive Variable	Primary PPx (N=26)a	Secondary PPx (N=16)
Immunosuppressive agent (at LET initiation), median no. (range)	2 (2–4)	2 (2–3)
Steroid, no. (%)	26 (100)	16 (100)
Prednisone dose in mg, median (range)b	7.5 (5–625)	5 (5–1250)
Azathioprine, no. (%)	3 (11.5)	0
Belatacept, no. (%)	1 (3.8)	0
Calcineurin inhibitor, no. (%)	25 (96.2)	16 (100)
Tacrolimus	17 (65.4)	14 (87.5)
Cyclosporine	8 (30.8)	2 (12.5)
Mycophenolate, no. (%)	7 (26.9)	4 (25)
Sirolimus, no. (%)	1 (3.8)	0
Alemtuzumab (≤ 12 months before LET initiation), no. (%)	3 (11.5)	2 (12.5)
Anti-thymocyte globulin (≤ 6 months before LET initiation), no. (%)	3 (11.5)	1 (6.3)
High dose steroids (≤ 6 months before LET initiation), no. (%)	10 (38.4)	6 (37.5)

LET: letermovir, PPx: prophylaxis.

^aRepresents 26 episodes in 25 patients. One patient received letermovir for primary prophylaxis following both second and third bilateral orthotopic lung transplant surgeries.

^bReflects maximum daily prednisone dose equivalent within 1 month before letermovir initiation.

Primary prophylaxis with letermovir was initiated a median of 315 days (IQR 125–1139 days) after transplant (Table 3). In contrast, secondary prophylaxis began a median of 695 days (IQR 537–1156 days) post-transplant with only 2/16 (12.5%) episodes initiated in the first transplant year. Primary prophylaxis was continued for more than 6- and 12 months in 65.4% and 23.1% of episodes, respectively, and nearly half of secondary prophylaxis episodes (7/16, 43.8%) exceeded 12 months. Further, these data underestimate the total duration of prophylaxis because nearly half of the patients (20/41, 48.8%) remained on letermovir at the study end date.

Table 3.

Letermovir Prophylaxis Episodes (N=42)

Prophylaxis Variable	Primary PPx (N=26)	Secondary PPx (N=16)
LET initiation, median days post-transplant (IQR)	315 (125–1139)	695 (537–1156)
LET duration, median days (IQR)a	280 (91–353)b	290 (196–629)
LET median dose, mg (range)	480 (240–480)	480 (240–720)
Rationale for LET use, no. (%)
Myelosuppressionc	25 (96.2)	10 (62.5)
Viral resistance	0	6 (37.5)d
Other	1 (3.8)e	0
Successful completion of LET prophylaxis, no. (%)	5 (19.2)	3 (18.8)
Remain on LET prophylaxis at end of study, no. (%)	11 (42.3)	9 (56.3)
Early discontinuation of LET prophylaxis, no. (%)	10 (38.5)	4 (25)
Adverse effects	5 (19.2)f	0
Clinically significant CMV infection	0	1 (6.3)
Other	5 (19.2)g	3 (18.8)h
Low level CMV DNAemia on LET prophylaxis, no. (%)i	5 (19.2)	10 (62.5)

CMV: cytomegalovirus, IQR: interquartile range, LET: letermovir, PPx: prophylaxis.

^aDuration truncated at study completion date (5/15/20) for patients remaining on letermovir (n=20).

^bTwo patients had a lapse in letermovir therapy; duration reflects total time on letermovir.

^cLeukopenia was most common.

^dDocumented resistance mutations included both UL97 (H520Q [n=3], L595S [n=1], C630W [n=2], M460V [n=1], C592G [n=1]) and UL54 mutations (T503I [n=2], A987G [n=1]).

^eTransitioned to letermovir given worsening renal dysfunction.

^fAdverse effects were myelosuppression (n=2), nausea (n=1), lightheadedness and fatigue (n=1), and confusion and fatigue (n=1).

^gReasons include: affordability/lack of insurance coverage (n=3); inability to tolerate oral medications and renal function prohibitive to the use of intravenous LET formulation (n=1); and transition to ganciclovir prophylaxis at the time of third lung transplant (n=1).

^hReasons include: affordability/lack of insurance coverage (n=1); transition to hospice care (n=1); and loss to follow-up due to transfer to another medical center (n=1).

ⁱRange detected and less than 137 IU/mL to 403 IU/mL (excludes single episode of clinically significant CMV infection reported on secondary prophylaxis).

Myelosuppression, primarily leukopenia, was the most common rationale for letermovir prophylaxis (35/42, 83.3%), though viral resistance was a frequent indication for secondary prophylaxis (6/16, 37.5%) (Table 3). From initiation to cessation of letermovir prophylaxis, the median WBC count increased from 3.1 × 10ˆ9/L (IQR 2.0 × 10ˆ9/L – 5.0 × 10ˆ9/L) to 5.0 × 10ˆ9/L (IQR 3.4 × 10ˆ9/L - 7.3 × 10ˆ9/L), respectively, reflecting a statistically significant increase in WBC counts during letermovir prophylaxis (median increase 1.4 × 10ˆ9/L; p < 0.001). Median hemoglobin values during letermovir prophylaxis trended upwards from 10.4 g/dL to 10.8 g/dL (median increase 0.4 g/dL; p = 0.06). The median platelet count remained stable at 191 × 10ˆ9/L at the start and finish of letermovir prophylaxis (p = 0.55).

At the close of the study, 8 (19%) letermovir prophylaxis courses had been successfully completed and 20 (48.8%) were ongoing (Table 3). The remaining 14 (33.3%) episodes necessitated early cessation of letermovir prophylaxis. Only 5 of 42 total episodes (11.9%) were stopped early due to perceived adverse effects from letermovir, including myelosuppression (n=2), nausea (n=1), fatigue and lightheadedness (n=1), and fatigue and confusion (n=1). An additional 4 (9.5%) episodes were stopped early due to lack of insurance coverage. Only one patient stopped letermovir due to clinically significant breakthrough CMV infection (Figure 1). This patient was a heart transplant recipient who had previously completed over three weeks of treatment with foscarnet for a ganciclovir-resistant (UL97 H520Q genotypic mutation) CMV infection, including CMV DNAemia without documented end-organ disease. Quantitative plasma CMV PCR testing was negative 4 days before letermovir secondary prophylaxis was initiated, but DNAemia became detectable (<137 IU/mL) and rose further to 637 IU/mL on days 3 and 10 of letermovir therapy, respectively. After day 10, letermovir prophylaxis was stopped and foscarnet treatment was re-initiated. This patient had end-stage renal disease requiring renal replacement therapy for which specific letermovir dosing adjustments are not available in the product labeling.[8] The patient was maintained on tacrolimus and initially received letermovir 240mg daily with an increase in the dose to 480mg daily on day 5 of therapy. No letermovir specific CMV resistance testing was performed, and the patient did not develop CMV end-organ disease.

Figure 1.

Clinically Significant Breakthrough CMV Infection on Letermovir Secondary Prophylaxis (n=1)

Legend: ● – undetected (negative) value; ○ - detected but not quantifiable value; - quantifiable value; dashed line represents the lower limit of quantification of the assay (137 IU/mL); NA: not available.

In addition, low level, transient CMV DNAemia occurred in 15 episodes of letermovir prophylaxis, including 5 primary and 10 secondary prophylaxis courses. CMV plasma PCR values ranged from less than 137 IU/mL to 403 IU/mL; however, only 3/15 (20%) episodes demonstrated quantifiable CMV DNAemia (Figure 2A-C). The remaining 12/15 (80%) episodes demonstrated detectable plasma CMV DNAemia that was below the lower limit of quantification of the assay (i.e., 137 IU/mL at DUH and 200 IU/mL at external labs). In all cases, prophylaxis was continued without the development of clinically significant breakthrough CMV infection.

Figure 2.

A-C: CMV DNAemia (quantifiable) on Letermovir Prophylaxis Without Clinically Significant Breakthrough CMV Infection (n=3)*

A. Primary letermovir prophylaxis with peak CMV DNAemia (300 IU/mL) on day 108/220 of therapy; B. Secondary letermovir prophylaxis with peak CMV DNAemia (228 IU/mL) on day 5/149 of therapy; C. Secondary letermovir prophylaxis with peak CMV DNAemia (403 IU/mL) on day 33/291 of therapy.

*CMV resistance testing to assess for letermovir resistance was not performed during the demonstrated letermovir prophylaxis episodes.

Legend: ● – undetected (negative) value; ○ - detected but not quantifiable value; - quantifiable value; arrow indicates day of letermovir cessation.

Discussion:

This cohort represents the largest evaluation of letermovir prophylaxis in thoracic organ transplantation published to date. In this retrospective cohort of 41 transplant recipients, letermovir was an effective prophylactic therapy when applied for both primary and secondary prophylaxis, despite nearly half of patients (19/42 episodes, 45.2%) receiving augmented immunosuppressive therapy for rejection in the preceding 12 months. Letermovir was most often applied in patients with myelosuppression, particularly leukopenia. WBC counts increased favorably over the course of prophylaxis, in many episodes allowing for reinstitution of antimetabolite therapy. Further, letermovir prophylaxis was often applied for extended periods of time and was generally well tolerated.

Experience with letermovir prophylaxis in SOT is limited, primarily consisting of single-center retrospective case reports and series with mixed results.[10–12, 16, 17] In our study, letermovir was effective in preventing CMV disease with clinically significant breakthrough CMV infection occurring in only 1 (2.4%) patient. However, Aryal et al.[10] reported failure in 3 of the 8 (37.5%) thoracic organ transplant recipients receiving letermovir prophylaxis, and Hofmann et al. [17] described breakthrough CMV infection in 2 renal transplant recipients receiving letermovir, the latter with documented emergence of UL56 terminase mutations encoding C325Y, known to confer high level letermovir resistance. All of these breakthrough cases, including our single case, occurred in high risk patients (D+/R-) receiving letermovir for secondary prophylaxis. For primary CMV prophylaxis, a single-center, matched cohort study of letermovir versus valganciclovir in SOT recipients demonstrated similar efficacy between letermovir (n=26) and valganciclovir (n=52) with breakthrough CMV in 8.7% and 13.5% (p=0.71), respectively. However, this study primarily evaluated renal transplant recipients and included only three thoracic organ transplant recipients.[12] An ongoing phase 3 randomized controlled trial (NCT03443869) evaluating the efficacy and safety of primary prophylaxis with letermovir plus acyclovir versus valganciclovir in high risk renal transplant recipients may provide additional useful data.[18]

Reasons for clinically significant breakthrough CMV infection while on letermovir prophylaxis are likely multifactorial and similar to explanations for failure of valganciclovir prophylaxis, including high risk CMV serostatus, augmented immunosuppressive therapy, and suboptimal antiviral exposure.[10, 17, 19] The importance of adequate antiviral exposure and medication compliance cannot be overstated with letermovir due to its low genetic barrier for resistance, the latter a notable culprit for failure when letermovir has been utilized for treatment of CMV infection.[20, 21] Suboptimal exposure may have contributed in our patient who failed letermovir secondary prophylaxis. This patient had end-stage renal disease necessitating hemodialysis, a scenario with limited pharmacokinetic data available to guide dosing.[8, 22] The patient was initiated on half of the recommended standard letermovir dose and quickly developed rising CMV DNAemia. In contrast, transient low level CMV DNAemia (range <137 IU/mL to 403 IU/mL) occurred in one-third of letermovir prophylaxis episodes in this study without subsequent development of any clinically significant breakthrough CMV infections. The significance of low level DNAemia in this setting remains uncertain, including the potential impact of “indirect” effects of CMV infection, such as acute allograft rejection and chronic lung allograft dysfunction, as well as the risk of promoting antiviral resistance [2, 23].

Due to the complexity of the SOT population and potential for multiple confounding variables, prospective controlled trials are indicated to better assess important outcomes associated with use of letermovir for CMV prophylaxis. For example, a controlled trial could help to determine the relationship between immunosuppression and efficacy of letermovir prophylaxis, especially given the potential for many thoracic organ transplant recipients with myelosuppression to concomitantly initiate letermovir and require changes in antimetabolite therapy. In addition, the clinical trial setting allows for comprehensive resistance analyses, which are critical amidst the expanding use of letermovir prophylaxis and demonstration of variant CMV strains associated with letermovir resistance. Notably, Douglas et al. [24] described a novel UL56 variant, E237G, which resulted in decreased susceptibility to both letermovir and ganciclovir, a concern not previously appreciated given the distinct viral targets of these therapies.

This study had four primary limitations. First, our analysis was a single-center retrospective analysis of only 41 patients; however, this cohort represents the largest analysis of CMV prophylaxis with letermovir to-date in the thoracic organ transplant population. Second, our evaluation was limited to adverse effects that resulted in termination of therapy rather than a comprehensive evaluation of all adverse effects during the study period. However, retrospective evaluation of the adverse effects of letermovir and delineation of causality is difficult in this complex transplant population. Third, the application of letermovir was typically late in the post-transplant period, with only 5 (11.9%), 9 (21.4%), and 16 (38.1%) of 42 total episodes initiated within the first 3-, 6-, and 12-months following transplant, respectively. Failure of letermovir prophylaxis may occur more often early after transplant when risk of CMV infection is higher [2–4]. Finally, the application of indefinite primary and secondary prophylaxis in lung transplant recipients is not a universal practice across transplant centers, potentially limiting generalizability of these data.

In summary, letermovir was a well-tolerated and effective alternative for CMV prophylaxis in thoracic organ transplant recipients with myelosuppression or a history of antiviral resistance to ganciclovir and valganciclovir. Additional prospective studies in thoracic and other SOT populations are necessary.