What is the data regarding use of Letermovir in solid organ transplant patients? Is there any data in pediatric solid organ transplant patients?

Comment by InpharmD Researcher

Use of letermovir in solid organ transplant patients has generally resulted in efficacious cytomegalovirus (CMV) prophylaxis without risk of increased adverse events (see Tables 1-5), and letermovir has been reported noninferior to valganciclovir for prevention of CMV disease in this patient population. Data specific to pediatric transplant patients is scant, and comprised of case reports that suggest favorable treatment outcomes. Still, more data is required to determine optimal dosing as primary CMV prophylaxis, as well as long-term safety with use.

Background

A 2024 review provides a comprehensive analysis of the roles of letermovir in the management of cytomegalovirus (CMV) infection among solid organ transplant (SOT) recipients. Letermovir is CMV-specific and does not affect other herpesviruses like herpes simplex or varicella-zoster, necessitating the concurrent use of antiviral agents, such as valacyclovir. As a prophylactic agent, letermovir has been used off-label for secondary prophylaxis in SOT recipients who are at high risk of CMV relapse after treatment for CMV infection. In these instances, letermovir has been shown to reduce the frequency of CMV recurrence when viral loads were adequately suppressed, although treatment-resistant mutations, particularly in the UL56 gene, have emerged in some patients. Additionally, letermovir’s oral availability has provided a more convenient option for outpatient care, substantially reducing hospitalization durations when transitioned from intravenous foscarnet therapy. However, breakthrough infections and drug resistance remain concerns in certain cases, especially when letermovir is used as secondary prophylaxis or initiated at high viral loads, highlighting the importance of careful patient monitoring and viral load assessments. [1]

Initially approved in 2017 for CMV-seropositive hematopoietic stem cell transplant (HSCT) recipients, letermovir subsequently gained FDA approval in 2023 for CMV prophylaxis in high-risk CMV D+/R− kidney transplant recipients. In a pivotal Phase 3 randomized clinical trial involving 601 CMV D+/R− kidney recipients (Table 1), letermovir demonstrated comparable efficacy to valganciclovir in preventing CMV disease (10.4% vs. 11.8%, respectively) and was associated with significantly lower incidences of neutropenia or leukopenia (25% vs. 64%). Additionally, fewer patients on letermovir discontinued treatment due to adverse events (4.1% vs.13.5% for valganciclovir). Despite some reports of breakthrough CMV DNAemia, letermovir did not show as high rates of resistance-associated mutations as valganciclovir, which highlighted its safety and efficacy for CMV prophylaxis in this population. Letermovir has also shown promise in off-label applications, including its use in non-kidney SOT recipients who developed myelosuppression during valganciclovir prophylaxis. Though breakthrough CMV DNAemia was occasionally reported in this setting, it was often asymptomatic and did not necessitate additional treatment. [1]

Another 2024 review also discusses the use of letermovir in transplant recipients. Real-world studies suggest letermovir is effective as prophylaxis against CMV across transplant settings. Smaller studies suggest potential for preemptive or resistant/refractory CMV treatment, alone or combined with other agents, achieving viral control in around 76% of cases. For kidney transplant recipients, letermovir was non-inferior to valganciclovir prophylaxis and had fewer side effects like leukopenia, leading to FDA approval for this use in 2023. Letermovir has high oral bioavailability and is well-tolerated, though drug interactions such as those with cyclosporine require dose adjustments. Its novel mechanism avoids cross-resistance with other antivirals. While resistance can emerge, rates remain low during prophylactic use but higher with treatment of active CMV. Data for SOT patients also appears more limited. [2]

A final 2024 article discusses the role of emerging antiviral agents for use in pediatric transplant patients. For letermovir, data appears limited to pediatric hematopoietic stem cell (HCT) patients and comprises a handful of case reports. Within the case reports, the outcomes were reported to be favorable, but letermovir’s effectiveness as primary prophylaxis remains unknown. While pediatric dosing has not yet been established, one study suggests adult dosing may be appropriate. The favorable safety profile is also limited to adult HCT and kidney transplants with a similar rate of acute kidney injury and hematological toxicities between treatment and placebo recipients. [3], [4], [5], [6]

References:

[1] Razonable RR. Current Perspectives on Letermovir and Maribavir for the Management of Cytomegalovirus Infection in Solid Organ Transplant Recipients. Drug Des Devel Ther. 2024;18:3987-4001. Published 2024 Sep 6. doi:10.2147/DDDT.S265644
[2] Royston L, Papanicolaou GA, Neofytos D. Refractory/Resistant Cytomegalovirus Infection in Transplant Recipients: An Update. Viruses. 2024;16(7):1085. Published 2024 Jul 5. doi:10.3390/v16071085
[3] Valencia Deray KG, Danziger-Isakov LA, Downes KJ. Current and Emerging Antiviral Agents in the Prevention and Treatment of Cytomegalovirus in Pediatric Transplant Recipients. J Pediatric Infect Dis Soc. 2024;13(Supplement_1):S14-S21. doi:10.1093/jpids/piad059
[4] Kuhn A, Puttkammer J, Madigan T, et al. Letermovir as Cytomegalovirus Prophylaxis in a Pediatric Cohort: A Retrospective Analysis. Transplant Cell Ther. 2023;29(1):62.e1-62.e4. doi:10.1016/j.jtct.2022.10.005
[5] Richert-Przygonska M, Jaremek K, Debski R, et al. Letermovir Prophylaxis for Cytomegalovirus Infection in Children After Hematopoietic Cell Transplantation. Anticancer Res. 2022;42(7):3607-3612. doi:10.21873/anticanres.15848
[6] P Daukshus N, Cirincione A, Siver M, et al. Letermovir for Cytomegalovirus Prevention in Adolescent Patients Following Hematopoietic Cell Transplantation. J Pediatric Infect Dis Soc. 2022;11(7):337-340. doi:10.1093/jpids/piac017

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the data regarding use of Letermovir in solid organ transplant patients? Is there any data in pediatric solid organ transplant patients?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-5 for your response.


Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients

Design

Randomized, double-masked, double-dummy, noninferiority, phase 3 trial

N= 601

Objective

To compare the efficacy and safety of letermovir with valganciclovir for prevention of cytomegalovirus (CMV) disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor

Study Groups

Letermovir (n= 289)

Valganciclovir (n= 297)

Inclusion Criteria

Documented CMV-seronegative adults (within 180 days prior to randomization) 18 years or older who received a kidney transplant from a CMV-seropositive donor

Exclusion Criteria

Previous hematopoietic stem cell transplant (HSCT) or solid organ, multiorgan, or double kidney transplant; history of or suspected CMV disease within 6 months before randomization; receipt of anti-CMV agents before randomization

Methods

Participants were randomized to receive letermovir (480 mg daily with acyclovir) or valganciclovir (900 mg daily, adjusted for kidney function) for up to 200 days after transplant, with matching placebos. CMV disease status, physical examination, vital signs, concomitant medications, and adverse events were assessed at all scheduled study visits.

Duration

Treatment: up to 200 days of treatment

Follow-up: 52 weeks

Outcome Measures

Primary: CMV disease through week 52

Secondary: CMV disease through week 28, time to onset of CMV disease through week 52

Baseline Characteristics  

Letermovir (n= 289)

Valganciclovir (n= 297)
Age, years 52.0 (18-82)

51.0 (18-78)

Men

72.9% 70.4%

White

86.6% 81.8%

Received Kidney from Deceased Donor

58.6% 61.3%

Received Lymphocyte-Depleting Induction Immunosuppression

45.9% 46.5%

Congenital Cystic Kidney Disease

17.8% 16.8%

Hypertension

14.4% 17.8%
Results

Endpoint

Letermovir (n= 289) Valganciclovir (n= 297)

CMV Disease

Through Week 28

Through Week 52

 

0

10.4%

 

1.7%

11.8%

Quantifiable CMV DNAemia

Through Week 28

Through Week 52

 

2.1%

31.8%

 

8.8%

37.7%

Leukopenia or neutropenia through Week 28

26% 64%

Prophylaxis discontinuation due to adverse events

4.1% 13.5%

The percentage of participants with committee-confirmed CMV disease through week 52 was comparable between groups (stratum-adjusted difference -1.4%; 95% confidence interval [CI] -6.5% to 3.8%).

Adverse Events

Diarrhea, tremor, urinary tract infection (letermovir group); leukopenia, diarrhea, tremor (valganciclovir group). Serious adverse events were similar between groups, including serious cardiac disorders. Fewer drug-related and serious drug-related adverse events with letermovir compared with valganciclovir.

Study Author Conclusions

Letermovir was noninferior to valganciclovir for prevention of CMV disease when taken for up to 200 days after transplant by adult high-risk CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, with less leukopenia or neutropenia. Additionally, participants who received letermovir did not develop resistance-associated substitutions and had a lower rate of CMV DNAemia, drug-related adverse events, and prophylaxis discontinuations due to adverse events, compared with valganciclovir.

Critique

The predominant use of white male participants, incomplete data from study participants, and the lack of formal assessment for long-term outcomes evaluated post-week 52 are all limitations that may confound or limit robustness of the findings. Additionally, only leukopenia or neutropenia were included when analyzing myelotoxicity; data on anemia and thrombocytopenia were not included for evaluation.

References:

Limaye AP, Budde K, Humar A, et al. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA. 2023;330(1):33-42. doi:10.1001/jama.2023.9106

Letermovir prophylaxis in solid organ transplant—Assessing CMV breakthrough and tacrolimus drug interaction

Design

Single-center, matched cohort study

N= 78

Objective

To assess the effectiveness and safety of letermovir in solid organ transplantation, specifically focusing on cytomegalovirus (CMV) breakthrough and tacrolimus drug interaction

Study Groups

Letermovir (n= 26)

Valganciclovir (n= 52)

Inclusion Criteria

Patients aged 18 years or older who received any type of organ transplant

Exclusion Criteria

Patients using letermovir for treatment, not prophylaxis; those using only pre-emptive treatment; those with a positive CMV PCR post-transplant prior to letermovir conversion; those using acyclovir prophylaxis

Methods

Patients were switched from valganciclovir to letermovir based on clinical judgment for hematologic toxicities. Letermovir was dosed at 480 mg daily. Valganciclovir was dosed at 450 mg daily for kidney and liver transplant recipients and 900 mg daily for heart transplant recipients.

Duration

Enrollment period: November 2017 to June 2020

Mean duration of letermovir was 69 days from conversion to the end of the 3 or 6-month prophylaxis period

Outcome Measures

Primary: Rate of CMV breakthrough infections while on prophylaxis

Secondary: Rate of leukopenia, doses of immunosuppression, rejection, non-CMV infection, renal function

Baseline Characteristics

 

Letermovir (n= 26)

Valganciclovir (n= 52)

   

Age

53.54 53.15    

Race

Black

White

Asian

Hispanic

 

50%

42.3%

3.8%

3.8%

 

55.8%

42.3%

1.9%

0

   

Male

61.5% 65.3%    

Organ

Kidney

Liver

Heart

Simultaneous liver-kidney

 

76.9%

15.4%

3.8%

3.8%

 

76.9%

15.4%

3.8%

3.8%

   

Antithymocyte globulin dose, mg/kg

4.75

4.98

   

CMV risk, high

80.8%

80.8%

   

Results

Endpoint

Letermovir (n= 26)

Valganciclovir (n= 52)

Odds ratio (95% confidence interval [CI])

p-Value

CMV breakthrough rate while on prophylaxis

2 (7.7%)

7 (13.5%)

0.54 (0.10 to 2.78) 0.710

Infected while on Prophylaxis (positive culture with treatment)

6 (23.1%)

9 (17.3%)

1.43 (0.45 to 4.58) 0.542

Positive for BK virus while on Prophylaxis

4 (15.4%)

6 (11.5%)

1.39 (0.36 to 5.45) 0.724

Rejection within 1 year post-transplant

3 (11.5%)

1 (1.9%)

6.66 (0.66 to 67.4) 0.105

GFR at the time of cessation of prophylaxis

54.5 (25.2%) 53.1 (27.1%) -- 0.824

Adverse Events

N/A

Study Author Conclusions

Patients converted from valganciclovir to letermovir did not show an increased rate of CMV breakthrough compared to a historical, matched cohort of patients remaining on valganciclovir. A significant drug interaction was noted with tacrolimus, leading to a recommendation to reduce the dose by 40-50% upon initiation of letermovir.

InpharmD Researcher Critique

Limitations included its retrospective nature, small sample size, difficulty in obtaining insurance approval for letermovir, use of "mini dose" valganciclovir limits generalizability, secondary rejection outcome which may not fully represent 1-year rejection rates, and inability to determine if letermovir is non-inferior to valganciclovir when started de novo post-transplantation.



References:

Winstead RJ, Kumar D, Brown A, et al. Letermovir prophylaxis in solid organ transplant-Assessing CMV breakthrough and tacrolimus drug interaction. Transpl Infect Dis. 2021;23(4):e13570. doi:10.1111/tid.13570

 

Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients

Design

Single-center, retrospective cohort study

N= 204

Objective

To assess the efficacy and safety of letermovir (LTV) compared to valganciclovir (VGC) for cytomegalovirus (CMV) primary prophylaxis in lung transplant (LTX) recipients

Study Groups

Valganciclovir (n= 175)  

Valganciclovir to letermovir (n= 29)

Inclusion Criteria

Adult primary LTX recipients transplanted between January 1, 2015, and July 30, 2022, with CMV risk (D+ and/or R+)

Exclusion Criteria

Low CMV risk (D-/R-), survived <90 days post-transplant, or transferred care before prophylaxis withdrawal
Methods

Patients received VGC 900 mg daily (renally dose adjusted) starting on postoperative day 1 for 1 year. If VGC was not tolerated due to myelosuppression, patients were transitioned to LTV 480 mg daily.

Duration

April 1, 2015 to July 30, 2022

Mean duration of VGC prophylaxis: 331 days

Mean duration of LTV prophylaxis: 168 days

Outcome Measures

Primary: Leukopenia, severe leukopenia, neutropenia requiring granulocyte colony-stimulating factor (GCSF)

Secondary: Thrombocytopenia, devere thrombocytopenia, lymphopenia

Baseline Characteristics  

Valganciclovir (n= 175)

Valganciclovir to letermovir (n= 29)  

Age, years

56.41 ± 12.7 59.3 ± 11.5  

Female

79 (45.1%) 16 (55.2%)  

Race/Ethnicity

White

Black or African American

Asian

Hispanic or Latino

Other

 

101 (57.7%)

17 (9.7%)

14 (8.0%)  

35 (20.0%)

8 (4.6%)

 

22 (75.9%)

4 (13.8%)

1 (3.4%)  

2 (6.9%)

0

 

Indication for transplant

Obstructive lung disease

Pulmonary vascular disease

Cystic fibrosis and immunodeficiency disorders

Restrictive lung disease

COVID-19-induced pulmonary fibrosis

Other

 

46 (26.3%)

18 (10.3%)

9 (5.1%)  

76 (43.4%)

25 (14.3%)

1 (0.6%)

 

6 (20.7%)

4 (13.8%)  

1 (3.4%)  

11 (37.9%)

6 (20.7%)

1 (3.4%)

 

Transplant procedure

Single

Bilateral

 

63 (36.0%)

112 (64.0%)

 

13 (44.8%)

16 (55.2%)

 

Induction immunosuppression

Lymphocyte depleting

Non-lymphocyte depleting

 

6 (3.4%)

169 (96.6%)

 

1 (3.4%)

28 (96.6%)

 

CMV serostatus

D+/R-

D+/R+

D-/R+

 

39 (22.3%)

85 (48.6%)

51 (29.1%)

 

8 (27.6%)

14 (48.3%)

7 (24.1%)

 

Augmented immunosuppression during first year post-transplant*

48 (27.4%) 8 (27.6%)  

Rejection during first year post-transplant

Acute cellular rejection

Antibody-mediated rejection

 

59 (33.7%)

8 (4.6%)

 

6 (20.7%)

1 (3.4%)

 

 *Augmented immunosuppression = anti-thymocyte globulin, bortezomib, carfilzomib, eculizumab, rituximab.

Results

Endpoint

Valganciclovir (n= 175) Valganciclovir to letermovir (n= 29) p-value

Leukopenia

144 (82.3%) 17 (58.6%) 0.008

Severe leukopenia 

100 (57.1%) 9 (31.0%) 0.016

Neutropenia requiring GCSF administration

124 (70.9%) 15 (51.7%) 0.048

Number of GCSF doses required per patient (IQR)

5 (3.0-12.0) 4 (2.50-8.0) 0.618

Number of GCSF doses required per day of PPX (IQR)

0.02 (0.01-0.04) 0.04 (0.01-0.08) 0.084

Lymphopenia

108 (90.8%)* 24 (82.8%) 0.212

Thrombocytopenia

52 (29.7%) 3 (10.3%) 0.051

Severe thrombocytopenia

17 (9.7%) 1 (3.4%) 0.454

Antiviral prophylaxis efficacy

Breakthrough CMV infection

Breakthrough CMV infection requiring treatment

Development of drug-resistant CMV

Post-prophylaxis CMV infection

Post-prophylaxis CMV infection requiring treatment

 

10 (5.7%)

9 (5.1%)

3 (30.0%)

43 (24.6%)

40 (22.9%)

 

1 (3.4%)

1 (3.4%)

0

11 (37.9%)

11 (37.9%)

 

0.955

1.0

1.0

0.199

0.132

Abbreviations: ANC, absolute neutrophil count; CMV, cytomegalovirus; GCSF, granulocyte colony-stimulating factor; IQR, interquartile range; PLT, platelet; PPX, primary prophylaxis; WBC, white blood cell count

*119 patients with necessary laboratory work for evaluation.

Adverse Events

See Results

Study Author Conclusions

In this single-center study, the incidence of leukopenia, severe leukopenia, and neutropenia requiring GCSF administration was reduced in patients converted to LTV for CMV prophylaxis compared to patients on VGC. Incidence of breakthrough and post-prophylaxis infections were comparable between groups. This study supports the use of LTV as a PPX agent in LTX recipients. Prospective trials are needed to determine whether LTV can be used as a first-line agent for CMV prophylaxis and whether LTV promotes improved morbidity and mortality related to CMV after LTX relative to VGC.

Critique

The study's limitations include its single-center, retrospective design, which restricts the generalizability of the findings. The small cohort of lung transplant recipients and the non-randomized approach introduce potential selection bias, while differing observation periods across patients may affect consistency in the data. The washout period could also contribute to bias, and the lack of documentation on maintenance immunosuppression regimens may overlook important factors influencing patient outcomes. Additionally, using a single threshold for CMV infections might oversimplify the assessment of infection risk and management in this population.

References:

Kleiboeker HL, Wang J, Borkowski N, et al. Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients. Transpl Infect Dis. Published online July 9, 2024. doi:10.1111/tid.14337

 

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients

Design

Observational, retrospective, multi-center study

N= 47

Objective

To evaluate the patterns of use and outcomes of letermovir (LET) treatment for cytomegalovirus (CMV) infection in transplant recipients

Study Groups

Study cohort (N= 47)

Inclusion Criteria

Receipt of an hematopoietic cell transplant (HCT) or solid organ transplant (SOT), use of LET to treat an established CMV infection, switched from another agent to complete therapy for an ongoing episode of CMV infection/disease

Exclusion Criteria

Started LET as primary or secondary prophylaxis after a distant episode of CMV infection, received less than 7 days of LET, poor adherence suspected

Methods

Patients were identified at 13 transplant centers, and demographic and outcomes data were collected. LET dosages varied, with most patients receiving 480 mg daily, and some patients increasing to 720 mg or 960 mg. Combination therapy was used in some patient cases. The median duration of LET treatment was 16.9 weeks for patients with a viral load >1,000 IU/mL.

Duration

Between January 2018 and January 2020

Outcome Measures

Primary: Virological failure (defined by specific criteria based on viral load changes)

Secondary: Clinical failure (i.e., symptomatic worsening or relapse of CMV symptoms)

Baseline Characteristics

 

Study cohort (N= 47)

     

Age, years (range)

56 (15-73)      

Male

32 (68%)      

White

35 (74%)      

Solid organ transplant

Lung

Kidney

Heart

Liver

Other*

 

48%

22%

7%

4%

19%

     

Stem cell transplant (no autologous)

Haploidentical

Cord blood

 

24%

29%

     

Graft vs. host disease

52%

     

Previous episode of CMV infection or disease

57%

     

Clinical indications for letermovir

Resistance

Clinically refractory

Intolerance to other treatments

Oral agent preferred

Other (combination therapy desired)

 

32%

13%

77%

19%

2%

     

CMV treatment at letermovir initiation

(Val)ganciclovir

Foscarnet

CMV immunoglobulin

Leflunomide

Other (CMV T cells, brincidofovir, intravitreal antivirals)

None

 

40%

34%

13%

6%

9%

17%

     

* One intestine, one pancreas alone, two kidney /pancreas, one kidney/lung

Results

 

 CMV Syndrome or DNAemia End organ disease

Endpoint

<1,000 IU/mL at LET start (n= 26) >1,000 IU/mL at LET start (n= 4) <1,000 IU/mL at LET start (n= 11) >1,000 IU/mL at LET start (n= 6)

Persistent or worsening symptoms while on LET

0 0 1 (9%) 3 (50%)

Death

Death direct result of CMV

Death indirect result of CMV

8 (31%)

0

1 (3%)

0

0

0

2 (18%)

0

0

3 (50%)

1 (17%)

2 (33%)

Clinical outcomes are provided by baseline CMV illness status.

Adverse Events

Diarrhea (resolved with discontinuation), increase in tacrolimus levels. Two deaths were reported due to invasive fungal infection, one as a consequence of renal failure due to foscarnet, and one death was reported at last known follow-up.

Study Author Conclusions

In summary, clinicians in transplant centers are using off-label LET primarily for patients intolerant of or resistant to available treatments. In situations where other less well tolerated agents can be used to reduce viral load to <1000 IU/ml, LET may be associated with favorable outcomes when used as “step down” therapy. Our series suggests that in situations where viral loads cannot be effectively reduced below 1000 IU/ml with other therapies, results are mixed. Randomized trials are required to confirm these observations, and further research to determine the effectiveness and safety of combination therapy and/or higher doses of LET is needed to better understand how to treat this challenging group of patients.

InpharmD Researcher Critique

Limitations of the study include that inherent to its observational design, as well as the small sample size of included patients. The lack of a control group and use of data from multiple centers, who utilize different CMV assays and specimen types across different temporal points, further introduces potential confounding.

References:

Linder KA, Kovacs C, Mullane KM, et al. Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. Transpl Infect Dis. 2021;23(4):e13687. doi:10.1111/tid.13687

 

Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients

Design

Observational, retrospective, single-center study

N= 10

Objective

To assess the practical application of letermovir as both primary and secondary prophylaxis against cytomegalovirus (CMV) in heart transplant recipients (HTR)

Study Groups

Primary prophylaxis due to neutropenia induced by valganciclovir (n= 2)

Secondary prophylaxis (n= 8)

Inclusion Criteria

All consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis

Exclusion Criteria

Patients who received letermovir as a treatment for active CMV infection

Methods

Letermovir was administered orally at 480 mg once a day (240 mg for patients treated with ciclosporine). CMV infection was identified by the presence of CMV replication, indicated by the detection of DNAemia. Neutropenia was defined as an ANC of <1000 cells/µL. Follow-up included monitoring CMV breakthrough infections, side effects, white blood cell counts, tacrolimus dosing, and QuantiFERON® CMV assay results.

Duration

June 2020 to January 2022

Follow-up: a minimum of 6 months after discontinuing letermovir or until the occurrence of CMV replication

Outcome Measures

Incidence of CMV breakthrough infections while on prophylaxis

Baseline Characteristics

 

All subjects (N= 10)

Age, years

48 

Transplant indication

Dilated cardiomyopathy

Ischemic heart disease

Hypertrophic heart disease

Restrictive heart disease

Arrhythmogenic right ventricular dysplasia

Others

 

30%

20%

10%

10%

10%

20%

Comorbidities at letermovir introduction

High blood pressure

Diabetes mellitus

Renal insufficiency (CrCl < 60 mL/min)

 

60%

20%

10% 

Induction immunotherapy

Anti-thymocyte globulin

Basiliximab

Addition of rituximab to anti-thymocyte globulin

 

90%

10%

10%

Maintenance immunosuppression at letermovir introduction

Corticosteroids

Calcineurin inhibitors

Antimetabolite

mTOR inhibitor

 

100%

100%

50%

30%

Abbreviations: ClCr, creatinine clearance (CKD-EPI)

Results

Median duration of letermovir administration: 8 months (range 3-12 months)

No CMV infection or disease occurred during primary or secondary letermovir prophylaxis.

Three patients on secondary letermovir prophylaxis experienced transient CMV blips, with no treatment changes required.

One patient discontinued letermovir due to gastrointestinal side effects. After stopping, three patients developed CMV infection at 18, 29, and 308 days, with co-infections (Pneumocystis pneumoniae in one and Gram-negative bacillus bacteremia in two) and one case of rejection. The other seven patients had no relapse (median follow-up of 9 [range 8-14] months).

All patients' neutropenia resolved after starting letermovir, with a 330% increase in neutrophil count by the 1-month follow-up.

Of the nine patients on tacrolimus, six required dose reductions after switching to letermovir. The average tacrolimus dose dropped from 0.07 mg/kg (±0.06) to 0.05 mg/kg (±0.06) within 7 days, a 14% reduction.

Adverse Events

See Results

Study Author Conclusions

This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

InpharmD Researcher Critique

The study's retrospective design, small sample size, limited generalizability, and potential selection bias may affect the reliability and applicability of the findings. 

References:

Saltiel G, Faure E, Assaf A, et al. Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients. Clin Transplant. 2024;38(5):e15327. doi:10.1111/ctr.15327