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Role of Letermovir for CMV Prophylaxis in Hematopoietic Stem Cell Transplantation

26 Sep 2019 1:52 PM | Deleted user

Authors: Avatar Patel, PharmD Candidate 2020; Marissa Olson, PharmD, BCOP and Kristan Augustin, PharmD, BCOP

Cytomegalovirus (CMV) is the largest β-herpesvirus transmitted by direct contact with infectious body fluids and is prevalent in over half of adults by the age of 40 years.1 CMV infection and disease are often characterized together, although they are not synonymous. CMV infection refers to the detection of viral antigens in tested bodily fluid or tissue, while CMV disease refers to symptomatic end-organ disease.2 While most individuals do not have signs or symptoms associated with CMV infection, primary infection leads to life-long latency. Reactivation of CMV infection occurs in 50-60% of patients after hematopoietic stem cell transplantation (HSCT) due to decreased CD4+ and CD8+ lymphocytes and represents the most common infection in HSCT.2 CMV reactivation is associated with increased morbidity and mortality post-HSCT. Common complications include pneumonia, colitis, and hepatitis. Risks for CMV reactivation include recipient and donor CMV seropositivity, transplant modality, and recipient’s age. Infection risk in HSCT patients can be broken down into three phases which include early phase (day 0 to day 30), intermediate phase (day 31 to day 100), and late phase (day 101 and after) post-transplant. Although CMV reactivation in HSCT patients can occur at any time, most reactivation is seen during the intermediate phase. Without prophylaxis, 80% of CMV-seropositive patients undergoing HSCT will have CMV reactivation.4

Prevention of CMV complications in HSCT patients can be approached by primary prophylaxis or preemptive therapy. Primary prophylaxis includes treating high risk patients, defined as recipients who are CMV-seropositive, during the first 100 days after transplant. Preemptive therapy is defined as the initiation of therapy after the detection of CMV viremia. Current National Comprehensive Cancer Network (NCCN) guidelines for preemptive therapy recommend valganciclovir or ganciclovir as first-line agents for the treatment of CMV viremia. Foscarnet or cidofovir are recommended as second-line agents for resistant CMV or for patients unable to tolerate first line therapy.5 The major limitations of preemptive therapy include weekly clinical follow-up and lack of protection against early CMV reactivation, which can lead to complications. While primary prophylaxis reduces early CMV reactivation, it does not prevent late onset reactivation, and use of antiviral therapies may be associated with significant adverse events such as myelosuppression and nephrotoxicity.6

Letermovir (PrevymisTM) was approved by the Food and Drug Administration (FDA) in November 2017 for CMV prophylaxis in HSCT CMV-seropositive recipients. Letermovir is the first non-nucleoside 3,4 dihydroquinazoline, reversible viral terminase inhibitor. It acts on the late stages of viral replication by inhibiting viral terminase at UL56 subunit which prevents viral DNA cleavage and results in inhibition of viral replication.6 Letermovir differs from other antiviral agents with CMV activity, such as ganciclovir, valganciclovir and foscarnet, in that it does not target UL54. Rather, it has a unique binding domain on UL56, which prevents cross-resistance with other agents.5 It is available as both an immediate-release tablet and intravenous formulation. It is initiated at 480 mg once daily beginning between day 0 and day 28 posttransplant and continued through day 100. Letermovir is eliminated via hepatic uptake OATP1B1/3 with a half-life of 12 hours.

In addition, letermovir is also a substrate of P-glycoprotein and a moderate inhibitor of CYP3A and CYP2C8 which can lead to drug-drug interactions. Trials have shown letermovir reduces the AUC of voriconazole by 50% and increases the AUC and Tmax of atorvastatin.2 Dosage should be decreased to 240 mg once daily in patients receiving concomitant therapy with cyclosporine as cyclosporine-mediated OTAP1B1/3 inhibition has been shown to double the AUC of letermovir.7 There are no dose adjustments recommended for creatinine clearance > 10 ml/min and mild or moderate hepatic impairment (Child Pugh class A or B). Letermovir is also not recommended in patients with severe hepatic impairment (Child Pugh class C) due to increased exposure.

NCCN guidelines updated in early 2019 added letermovir as a first-line agent for CMV prophylaxis in CMV-seropositive allogeneic HSCT recipients based on the results of a phase III study. The trial randomized 545 subjects in a 2:1 ratio to receive letermovir or placebo daily through week 14. The primary end point was the proportion of subjects with clinically significant CMV infection, defined as > 300 copies/ml via PCR testing, through week 24. Patients were stratified based on CMV disease risk and were eligible if they were CMV-seropositive and had an undetectable level of CMV DNA within 5 days of randomization. A decrease in clinically significant CMV infection at week 24 was observed in the letermovir group compared to the placebo group (37.5% vs. 60.6%, p < 0.001). In addition, all-cause mortality was lower at week 24 for patients receiving letermovir (10.2% vs. 15.9%, p < 0.03). Patients being treated for graft versus host disease (GvHD) or those with T-cell depleted grafts were found to have the greatest benefit from letermovir prophylaxis. However, the trial did show a rise in CMV infection when letermovir was discontinued after 100 days which may suggest the reduced benefit of letermovir prophylaxis when discontinued. There were no statistical significant differences in adverse effects between the two treatment groups.7

Letermovir has proven efficacy when used as CMV prophylaxis in HSCT CMV-seropositive recipients. It offers clinicians a therapeutic option without the significant toxicities seen with other antiviral treatments. Although the phase III trial showed a significant decline in rates of CMV infection and all-cause mortality at 24 weeks, there are still unanswered questions. Upon discontinuation of letermovir, high risk patients were more likely to have CMV reactivation. In addition, while this trial only evaluated letermovir for prevention of CMV in HSCT patients, future trials may assess the potential option to use letermovir as a treatment option due to the minimal adverse effect profile.

References

1. Centers for Disease Control and Prevention. Cytomegalovirus (CMV) and Congenital CMV Infection. www.cdc.gov/cmv/overview (accessed 2019 June 6).

2. Ljungman P, Boeckh M, Hirsch HH et al. Definitions of Cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2016;1(1):87-91.

3. Deleenheer B, Spriet I, Maertens J. Pharmacokinetic drug evaluation of letermovir prophylaxis for cytomegalovirus in hematopoietic stem cell transplantation. Expert Opinion on Drug Metabolism & Toxicology. 2018;14(12):1197-1207.

4. Styczynski J. Who is the patient at risk of CMV recurrence: A review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;7:1-16.

5. National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections (updated 2019). www.nccn.org/professionals/physician_gls/pdf/infections.pdf (accessed 2019 Jul 18).

6. Razonable RR. Role of letermovir for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Curr Opin Infect Dis. 2018;31:286-291.

7. Foolad F, Aitken SL, Chemaly RF. Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients. Expert Review of Clinical Pharmacology. 2018;11(10):931-941.

8. Marty FM, Ljungman P, Chemaly RF et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444. 


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