Use Of Letermovir Research Articles

Letermovir salvage therapy in the management of a case of cytomegalovirus ventriculitis complicated by drug resistance

Abstract Reported is a case of cytomegalovirus ventriculitis on a background of HIV infection. Sequencing demonstrated viral mutations conferring resistance to available therapies. Compassionate use of letermovir was attempted; though clinical improvement was observed the patient passed away. Sequencing demonstrated that known letermovir resistance mutations were not detected in this virus.

Prophylaxis vs preemptive therapy in prevention of CMV infection: new insight on prophylactic strategy after allogeneic hematopoietic cell transplantation

AbstractCytomegalovirus (CMV), the beta-human herpesvirus type 5 (HHV-5), is a major cause of morbidity in immunocompromised hosts, especially recipients of allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation. The standard-of-care approach to CMV prevention based on CMV surveillance-guided preemptive therapy is being challenged by the recent approval of letermovir (LMV) for primary prophylaxis. Real-word clinical data show dramatic improvement in the reduction of risk of CMV infection and any CMV viremia in all studies performed so far. LMV is the drug that is breaking the paradigm of preemptive therapy with shift to prophylaxis. A summary of reported data presented in 2019 annual meetings of American Society of Transplantation and Cellular Therapy (ASTCT), European Society for Blood and Marrow Transplantation (EBMT) and American Society of Hematology (ASH), as well as already published results, is presented in this review. A total number of 401 adult high-risk patients on primary prophylaxis after HCT were reported in 11 studies up to January 1, 2020. It was shown that fewer patients in the LMV arms had any CMV reactivation or need for CMV treatment compared with the any other prophylactic or preemptive approaches. In conclusion, LMV is much highly effective than CMV-guided preemptive therapy in preventing CMV infection and CMV disease. The use of LMV in prophylaxis results in an improvement in overall survival during the first 24 and 48 weeks. LMV has a favorable safety profile, as it does not cause myelotoxicity. Current guidelines of European Conference on Infections in Leukemia (ECIL7) recommend LMV for the use in prophylaxis of CMV infection in patients after allogeneic hematopoietic cell transplant.

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program.

Letermovir potently inhibits the cytomegalovirus (CMV)-terminase complex. Letermovir primary prophylaxis given for the first 3 months after allogeneic hematopoietic cell transplantation (HCT) has been shown to reduce clinically significant CMV infection and is well tolerated. Until now, only case reports or small retrospective series have been published on the use of letermovir for a secondary prophylaxis (SP) of CMV infection or diseases after HCT. Here we report the outcome of 80 consecutive CMV-seropositive adult patients included in the French compassionate program and who received letermovir as a SP after at least 1 CMV episode (infection or disease) since HCT. Letermovir was initiated at a median of 170 (49 to 1829) days after transplant and given orally for a median of 118 (26 to 396) days at the usual daily dose of 480 mg once daily and adjusted to 240 mg once daily when coadministered with cyclosporine. The donors were seronegative in 53% of the cases. Fifty patients had a current or previous graft-versus-host disease (GVHD) and 14 had experienced CMV disease since transplant. Four (5.5%) patients developed CMV breakthrough infections (n=1) or diseases (n=3) after the initiation of letermovir. In 3 of these 4 patients, further investigation of virologic resistance showed a CMV UL56 mutation C325Y or W, conferring the high-level letermovir resistance. One or more adverse reactions were declared by the local investigator in 15 (19%) patients. Only 2 patients stopped letermovir SP because of an adverse reaction (pruritus, 1; cytopenia, 1). In our experience, letermovir given as a SP may prevent a new CMV reactivation in a high-risk patient population and can be administered for several weeks, providing a bridge between the pre-emptive or therapeutic treatment of a CMV episode and CMV-specific immune reconstitution, giving time for tapering immunosuppressants. Prospective studies are required to confirm these results.

Letermovir for the Management of Cytomegalovirus-associated Uveitis

ABSTRACT Purpose: To investigate the use of letermovir 480 mg daily for the treatment of cytomegalovirus (CMV)-associated uveitis (AU). Methods: Retrospective case series of CMV-AU patients on letermovir. Results: Six eyes of five patients (mean age 54 years) were included. Mean follow-up time was 10 months. Four patients had CMV anterior uveitis and one patient had bilateral CMV retinitis. All were treated initially with valganciclovir 900 mg twice daily. Transition to letermovir was due to cytopenias (n = 3), transaminitis (n = 1), and persistent inflammation on valganciclovir (n = 1). At the initiation of letermovir, mean visual acuity (VA) was 0.35 logMAR and IOP was 14 mmHg. One of the six eyes had a recurrence of anterior uveitis due to self-discontinuation of letermovir. No adverse events were observed. At last follow-up, no patients had active inflammation. Mean VA was 0.08 logMAR and IOP was 9 mmHg. Conclusion: Letermovir may be an alternative treatment for CMV-AU in patients with persistent inflammation or side effects on valganciclovir.

Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients.

Cytomegalovirus (CMV) infection is common in thoracic organ transplant recipients. Valganciclovir and ganciclovir are used for both prophylaxis and treatment of this infection, but intolerance and treatment failure are common. Letermovir has been demonstrated to reduce the risk of CMV infection when used for prophylaxis in allogeneic hematopoietic cell transplantation. However, there are no data on its efficacy in thoracic organ transplantation. We examined the use of letermovir for either CMV prophylaxis (primary and secondary) or treatment in heart and lung transplant recipients at our institution from February 1, 2018, through December 31, 2018. Nine total patients received letermovir at our institution (8 lung transplant, 1 heart transplant) during the study period. Letermovir was prescribed for CMV prophylaxis in eight patients (primary prophylaxis in two patients and secondary prophylaxis in 6 patients), and for treatment of CMV DNAemia in two cases. One patient received letermovir for both secondary prophylaxis and treatment on separate occasions. Three out of 8 (37.5%) patients receiving letermovir for prophylaxis developed CMV DNAemia during prophylaxis. One patient treated for CMV disease had clinical failure with a sharp rise in serum CMV DNA PCR. The other patient treated for low-grade CMV DNAemia initially had a slight rise in CMV DNA PCR, but has since had a sustained response. No major side effects were experienced, and 2 patients reported minor side effects. Letermovir was well tolerated with only minor side effects reported; however, the rate of development of CMV DNAemia on prophylaxis was considerable. Further study of the dosing and efficacy of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is warranted.

Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review.

Cytomegalovirus (CMV) is a leading opportunistic infection in immune compromised patients, including allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT) recipients, where primary infection or reactivation is associated with increased morbidity and mortality. Antiviral drugs are the mainstay for the prevention of CMV infection and disease, most commonly with valganciclovir. However, valganciclovir use is often associated with adverse drug reactions, most notably leukopenia and neutropenia, and its widespread use has led to emergence of antiviral resistance. Foscarnet and cidofovir, however, are associated with nephrotoxicity. Letermovir, a novel CMV viral terminase inhibitor drug, was recently approved for CMV prophylaxis in allogeneic HSCT recipients. It has a favorable pharmacokinetic and tolerability profile. The aim of this paper is to review the evidence supporting the use of letermovir in allogeneic HSCT recipients, and how the drug impacts our contemporary clinical practice. In addition, we discuss the ongoing clinical trial of letermovir for the prevention of CMV in SOT recipients. The use of letermovir for treatment of CMV infection and disease is not yet approved. However, because of a unique mechanism of activity, we provide our perspective on the potential role of letermovir in the treatment of ganciclovir-resistant CMV infection and disease. Furthermore, drug-resistant CMV has emerged during use of letermovir for prophylaxis and treatment. Caution is advised on its use in order to preserve its therapeutic lifespan.

Use of Letermovir for CMV Prophylaxis or Treatment in Thoracic Organ Transplant Recipients

Purpose CMV infection is common among transplant recipients and may result in increased morbidity and mortality. Valganciclovir and ganciclovir are frequently used for viral prophylaxis or treatment. However, these agents can be difficult to tolerate due to myelosuppression. Letermovir, an anti-viral drug which inhibits CMV-terminase complex, has been demonstrated to reduce the risk of CMV infection in hematopoetic-cell transplantation. We sought to assess the utility of letermovir in thoracic organ recipients in whom valganciclovir and ganciclovir were not well tolerated or were ineffective due to resistance. Methods We examined our institutional experience with the use of letermovir for either CMV prophylaxis or treatment in heart and lung transplant recipients from February to September 2018. Results Nine total patients received letermovir during the study period (8 lung, 1 heart). Letermovir was administered for CMV prophylaxis in 8 instances and for treatment of CMV viremia in 2 instances (see Table). One patient received letermovir for both prophylaxis and treatment on temporally separate occasions. 3 of 8 (37.5%) of patients receiving letermovir for CMV prophylaxis developed viremia while on treatment. One patient treated for ganciclovir resistant CMV disease with letermovir had overt clinical failure with a sharp rise in serum CMV PCR. The other patient treated for low grade CMV viremia initially cleared but then relapsed with low grade viremia (CMV PCR 214). No major side effects were reported. 2 patients experienced minor side effects (1 edema, 1 fatigue). Conclusion Letermovir was well tolerated with only minor side effects reported in a population intolerant or resistant to conventional CMV prophylaxis and treatment. However, efficacy was poor, with a high rate of CMV viremia on therapy (50%). Further study of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is nonetheless warranted to better characterize its potential role in this high risk population.

Use of Letermovir as Salvage Therapy for Drug-Resistant Cytomegalovirus Retinitis.

Treatment options for drug-resistant cytomegalovirus (CMV) are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but its efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically confirmed resistance to letermovir while on therapy.

Efficacy and Pharmacoeconomic Impact of Letermovir for CMV Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients

Cytomegalovirus (CMV) seropositivity and early CMV reactivation after hematopoietic-cell transplantation (HCT) remain associated with increased mortality. Those at high risk include CMV seropositive recipient/donor pairs (CMV R+ or D+) and those on escalated immunosuppression (prednisone ≥ 20mg/kg) for graft versus host disease (GVHD). Historically, our institutional CMV reactivation rate (RR) was 63% in our high risk cohort, similar to national average. Prophylaxis with letermovir, a new CMV-antiviral therapy, significantly reduced the incidence of CMV reactivation and viremia in a prospective trial (Marty FM, et al. NEJM 2017). The purpose of this study was to assess CMV reactivation, defined as CMV viral load > 500 IU/mL, with letermovir prophylaxis and its pharmacoeconomic impact in an outpatient transplant program. This was a retrospective review of adult HCT patients receiving letermovir from December 2017-August 2018 at Vanderbilt University Medical Center. Use of letermovir was standardized at a program level. Therapy was used in high risk patients, undergoing HCT with matched-unrelated donor (MUD), cord blood donor or haploidentical donor transplants with no active CMV reactivation prior to initiation and no anti-CMV treatment post-HCT. Primary endpoint compared CMV RR to historical controls utilizing a two-sided t-test. Secondary outcomes evaluated logistics and cost impact. 30 patients met entry criteria (26 CMV R+, 21 D+), RR was significantly lower than our historical control (20% vs 63%; p = 0.0003). Median time to reactivation was 38 days post-HCT (29-58). 4 of the 6 patients with reactivation received induction therapy with ganciclovir (50%), valganciclovir (25%), or letermovir (25%, peak viral load 740 IU/mL) for ∼40 days (31-52). All were CMV R-/D+ with AML and received HCT from MUD (75%) or haploidentical donors (25%). The remaining 2 patients (CMV R+/D+) had low level reactivation (137-500 IU/mL) and continued letermovir through day 100 without additional CMV treatment. Patients started letermovir by day 14 post-HCT (5-65) with a median 83 days (7-158) of prophylaxis. 3 patients received letermovir as secondary prophylaxis due to prior CMV reactivation or escalated immunosuppression for GVHD. Of those patients, reactivation occurred in 1 patient (AML MUD transplant; CMV D-/R+) who had 2 reactivations while on foscarnet therapy. No letermovir resistance was observed. Letermovir copay was between $10 and $360/month. 76% of prescriptions required prior authorization, 19% monetary grant, 18% patient assistance. Majority had private insurance (49%) and Medicare/Medicaid (36%) with a median of 3 days for approval and 5 days from prescription submission to patient medication pick-up. Primary prophylaxis with letermovir is associated with significantly lower RR compared to historical controls and is financially feasible with dedicated pharmacy services.

Letermovir for Secondary Cytomegalovirus (CMV) Prophylaxis in a Pediatric Stem Cell Transplant Patient

Patients who undergo stem cell transplants are at a significant risk of infections. Cytomegalovirus (CMV) is an organism of particular concern in this population. Current treatments options for CMV include ganciclovir, valganciclovir, foscarnet, and cidofovir. These treatment options have adverse effects such as myelosuppression or nephrotoxicity, making them less than ideal as a treatment options. Increasing rates of drug resistance is another concern. The need for alternative treatment options is paramount. Many patients require secondary prophylaxis. Letermovir is a newly approved CMV DNA terminase complex inhibitor indicated for prophylaxis of CMV infection and disease in adults. Its role in secondary prophylaxis has not been clearly defined. We report the case of an 11-year old male who had undergone a 4/6 HLA-matched cord blood transplant for Fanconi Anemia. The patient developed CMV viremia that later progressed to CMV colitis and pneumonitis. He was initially treated with ganciclovir then was found to have UL97 mutation. He was then switched to foscarnet for induction therapy, to which the patient showed a good response. The patient was subsequently transitioned to cidofovir for maintenance therapy where CMV viremia recurred. Foscarnet was re-initiated with good response then transitioned to cidofovir maintenance therapy. Unfortunately, CMV viral load began to increase prompting a change to high-dose ganciclovir. Due to concerns for myelosuppression with using high-dose ganciclovir he was switched back to foscarnet. While on foscarnet the patient had nephrotoxicity and electrolyte disturbances and the decision was made to re-initiate high-dose ganciclovir. When the patient's CMV viral load was undetectable the patient was transitioned to letermovir 480 mg daily with successful suppression of CMV viral load. Letermovir has been well tolerated and the patient has experienced no adverse effects associated with it. The patient has not required further therapy for CMV viremia since starting letermovir. Letermovir prophylaxis was stopped after four months of therapy. The patient's CMV viral load began to rise after stopping for one month with the peak at 381 copies/mL. After restarting letermovir the CMV viral load became undetectable and has remained so. Letermovir could be useful in secondary prophylaxis in pediatric patients with ganciclovir-resistant CMV who are at risk of recurrences. Further investigation is warranted for the use of letermovir in the pediatric population.

Preliminary Outcomes of Letermovir Use for Cytomegalovirus Prophylaxis: A Retrospective Assessment at a Single Center

Introduction Cytomegalovirus (CMV) is associated with significant morbidity and mortality in the hematopoietic cell transplant (HCT) population. In the absence of prophylaxis, reactivation occurs in upwards of 80% of seropositive allogeneic HCT recipients and primary infections in roughly 15% of CMV-mismatched HCTs. Agents used to prevent clinically significant CMV (csCMV) including ganciclovir and foscarnet can be associated with toxicities including renal dysfunction and myelosuppression. Letermovir is a novel antiviral targeting the viral terminase complex and has demonstrated efficacy in preventing csCMV in adult CMV seropositive allogeneic HCT recipients with minimal associated toxicities. Objectives To describe a single center experience of the use of letermovir as primary and secondary prophylaxis in adult allogeneic HCT recipients. Methods This retrospective analysis assessed 25 adult HCT patients receiving letermovir for primary or secondary prophylaxis between January 1, 2018 and September 24, 2018. Primary prophylaxis per hospital protocol was given through approximately d+100 in CMV seropositive recipients and also allowed in CMV seronegative recipients with seropositive donors. csCMV was defined as CMV viremia necessitating preemptive therapy or CMV disease. Patients were evaluated for development of csCMV on letermovir prophylaxis, early cessation of prophylaxis due to perceived toxicities, and development of csCMV post-cessation of primary prophylaxis. Results Twenty-two patients received letermovir for primary CMV prophylaxis. The primary underlying disease was AML (7/22, 32%). CMV serostatus was as follows: D-/R+ (9/22, 41%), D+/R+ (9/22, 41%), D+/R- (4/22, 18%). Letermovir was initiated ata median of 5.5 days post-transplant. Median letermovir duration was 95 days post-transplant. Early cessation due to perceived toxicities occurred in 41% (7/22) of patients. Reasons for early discontinuation were ongoing cytopenias (4/7, 44%) and nausea (3/7, 33%). No csCMV developed during therapy. In patients completing the intended primary prophylaxis (n = 10), thus far no patients have developed csCMV within a median duration of 150 days post letermovir cessation. Three patients received letermovir for secondary prophylaxis. All were CMV seropositive and high risk on basis of haploidentical donors (2/3, 67%) and use of cord blood (1/3, 33%). Therapy was initiated a median of 57 days post-transplant with no patients developing csCMV on therapy. Conclusions Letermovir was an effective antiviral in both primary and secondary CMV prophylaxis and was generally well tolerated. Side effects directly related to letermovir were difficult to assess in this complex patient population. Close monitoring is required following cessation of primary prophylaxis. Prospective studies defining the optimal duration for letermovir prophylaxis are needed.

A Single Center Experience of Letermovir for the Prevention of CMV Infection in CMV-Seropositive Allogeneic Cell Transplant (Allo-HCT) Recipients

Introduction and Objectives Letermovir (LTV) is the first agent in the class of anti-CMV viral terminase inhibitors and was recently approved in the U.S. for the prevention of CMV infection in CMV-seropositive allo-HCT recipients. In the phase III study, use of LTV after transplant through day 100 resulted in significantly less CMV infections and decreased mortality at week 24 when compared to placebo. In March 2018, LTV was recommended for all CMV-seropositive allo-HCT recipients at our institution. We sought to evaluate the impact of this strategy on our patients. Methods We retrospectively evaluated all adult patients who had an allo-HCT and reached day 100 post-transplant from March – September 2018. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia or disease that resulted in initiation of anti-CMV therapy. All patients had twice-weekly CMV viral load monitoring. Patients were followed up to day 100 from HCT. Results A total of 74 patients underwent allo-HCT and reached day 100 post-transplant by end of September 2018. Fifty-three patients (72%) received LTV prophylaxis, and 21 patients (28%) did not. The most common reason for lack of LTV was insurance approval and financial issues (57%). The median age was 59 years (range: 45-66) in both groups, and 49% were male. Transplant types were similar between groups with the most common being from matched unrelated (46%) and matched related (31%) donors. The median time to engraftment was the same in both groups at 15 days (range: 12-19). Patients on LTV prophylaxis had less CS-CMVi than patients not on prophylaxis (21% vs. 52%, p = 0.01). Although not statistically significant, less patients on LTV prophylaxis had probable and proven CMV disease (LTV, 6% vs. no prophylaxis, 10%; p = 0.55), and less were hospitalized for treatment of CMV infections (LTV, 7% vs. no prophylaxis, 12%; p = 0.57). All-cause mortality at day 100 was numerically higher in the group without prophylaxis (no prophylaxis, 14% vs. LTV, 4%; p = 0.10). Conclusions This is the first ongoing study evaluating the impact of LTV for prevention of CMV infection. We found that LTV reduced the incidence of CS-CMVi including a trend towards decreased mortality. Given its demonstrated benefits, LTV should be considered in all CMV-seropositive allo-HCT recipients.

Breakthrough CMV Infections on Letermovir Prophylaxis in CMV-Seropositive Allogeneic Hematopoeitic Cell Transplant (allo-HCT) Recipients

Introduction Letermovir (LTV) is the first agent approved for CMV prophylaxis (ppx) in CMV-seropositive allo-HCT recipients. In the phase III study, the use of LTV after transplant through day 100 resulted in significantly less episodes of CMV infection and decreased mortality at week 24 when compared to placebo. Although clinical trials demonstrated the benefit of LTV, we sought to determine the efficacy of this agent and to characterize breakthrough CMV infections at our institution. Objectives and Methods This is a retrospective study evaluating the characteristics of breakthrough CMV infections in allo-HCT recipients who did or did not receive LTV for ppx. We reviewed all allo-HCT recipients who were eligible for LTV starting in March 2018 and who had reached day 100 by September 2018. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia or disease that resulted in initiation of anti-CMV therapy. All patients received twice-weekly pre-emptive monitoring for CMV viremia. Results A total of 74 CMV-seropositive patients underwent allo-HCT and reached day 100 by September 2018. Fifty-three patients (72%) received LTV, and 21 patients (28%) did not. Patients on LTV for ppx were less likely to have CS-CMVi when compared to patients on no ppx (11 patients (21%) vs. 11 patients (52%), p = 0.01). The median viral load (VL) at initiation of anti-CMV therapy was similar between the 2 groups (median CMV DNA IU/mL: 1078 on LTV vs. 914 on no ppx, p = 0.57). CMV resistance genotype panels were sent after breakthrough in 8 patients (3 on LTV, 5 on no ppx) and no mutations were detected. Less patients who were on LTV ppx had a second CMV event when compared to patients who were on no ppx [1/11 (9%) vs. 3/11 (27%), respectively]. All-cause mortality was numerically higher in patients who had positive CMV VL and were not on LTV for ppx (12% no ppx vs. 7% on LTV, p = 0.57). Conclusions Patients who were on LTV for prophylaxis had less CS-CMVi, less episodes of CMV infections and trend towards lower all-cause mortality by day 100. Larger sample size is needed to further define breakthrough CMV infections while on LTV and the need for anti-CMV therapy.