letermovir and Viremia

The efficacy of different letermovir (AIC246, MK8228) doses (60, 120, and 240 mg/day) against human cytomegalovirus (HCMV) was evaluated in a recent phase 2b dose-range-finding prophylaxis study in stem-cell transplant recipients. Here we report the genotypic and phenotypic characterization of 15 viral breakthroughs considered to be virological failures.. Direct sequencing of an HCMV open reading frame UL56 region that included amino acids 230-370 and thus encompassed all known letermovir resistance mutations was followed by marker-transfer experiments to assess the impact of the identified sequence polymorphisms on viral fitness and susceptibility to letermovir.. UL56 genotyping was successful for 12 of 15 patients. Six amino acid substitutions were detected in 5 patients. In 1 subject from the 60-mg-dose group, the known letermovir resistance mutation V236M was identified subsequent to a wild-type viremic episode. The remaining 5 sequence variants (L134V, S227I, Q228H, R410G, and D414N) were shown to be inert with regard to letermovir susceptibility, thus representing natural polymorphisms.. Our findings represent the first case of a letermovir resistance mutation emerging in the clinic, apparently because of a suboptimal prophylactic dose (60 mg/day). This is in agreement with the trial's efficacy analyses, findings of which suggest that letermovir doses of 60 mg/day and 120 mg/day are suboptimal for prophylaxis whereas a dose of 240 mg/day appears to achieve complete suppression of viremia.

Topics: Acetates; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Resistance, Viral; Humans; Open Reading Frames; Quinazolines; Viral Load; Viremia

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-of-concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.

Topics: Acetates; Adult; Aged; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Kidney Transplantation; Male; Middle Aged; Opportunistic Infections; Quinazolines; Viral Load; Viremia

Cytomegalovirus (CMV) infection significantly impacts the morbidity and mortality of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Despite monitoring and pharmacologic prophylaxis with drugs such as valganciclovir or ganciclovir, rates of early CMV reactivation have continually persisted, contributing to increased rates of morbidity and mortality in allogeneic-HSCT patients. This study evaluates the outcomes of letermovir in preventing CMV reactivation and CMV-related complications in HSCT recipients with initiation of therapy at +21 days in high-risk patients.. We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received allogeneic-HSCT from 2018 to 2020 with subsequent serial CMV monitoring and treatment. CMV reactivation was determined in patients if they had clinically significant serum CMV viremia (viremia requiring treatment) or organ involvement by day+100. Primary endpoint assessed was day+100 rates of CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, and incidence of GVHD. Descriptive statistics were used to compare characteristics between groups used in this study, with a significance level of α = 0.05.. Between 2018 and 2020, 116 adult HSCT recipients were reviewed. 51% were male and 49% were female; donor sources consisted of 27% match related donor (MRD) 28% match-unrelated donor (MUD), and 45% haploidentical donor. Of the 116 patients, 92 were identified as high-risk for CMV reactivation. 71 patients received letermovir prophylaxis, and 21 patients received no prophylaxis. In high-risk patients, after adjusting for GVHD status and transplant type, patients that received letermovir had no statistically significant difference of having D + 100 CMV reactivation compared to patients that did not receive letermovir. 1.02 (95% CI: 0.35, 3.20) (p = 0.97). Moreover, there were no statistically significant difference observed between letermovir treatment and 1-year OS, 1-year RFS, and incidence of GVHD.. Patients in the high-risk letermovir group had outcomes that were comparable to the lower risk "non-letermovir" group. There was no significant difference in CMV D + 100 reactivation between high-risk patients who did not receive letermovir compared to the patients who did. While other studies have shown that early initiation of letermovir may be associated with improved outcomes, our study shows that the use of letermovir with initiation at 21 days may not necessarily translate to improved secondary outcomes such as overall survival. Further prospective studies evaluating the time of initiating therapy and outcomes are needed.

Topics: Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Prospective Studies; Retrospective Studies; T-Lymphocytes; Transplantation, Homologous; Unrelated Donors; Viremia

Currently available anti-cytomegalovirus (CMV) agents are sometimes poorly tolerated, owing to their side effects. Letermovir is a novel anti-CMV drug that is only approved for CMV prophylaxis in hematopoietic stem cell transplant recipients, with fewer side effects. We report the case of a heart transplant recipient with UL97 mutation (L595F) ganciclovir-resistant cytomegalovirus colitis who was successfully treated with off-label use of letermovir. In treating CMV infection or disease with letermovir, a transient rise or lag in the clearance of CMV-DNA polymerase chain reaction levels has been observed. Our case suggests that CMV-pp65 antigenemia can be an additional marker of treatment efficacy.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Heart Transplantation; Humans; Mutation; Viremia

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Heart Transplantation; Humans; Tacrolimus; Transplant Recipients; Valganciclovir; Viremia

Letermovir is an antiviral agent indicated for primary prophylaxis of cytomegalovirus (CMV) infection and disease in adult allogeneic hematopoietic stem cell transplant recipients. In this case, UL97 mutation that conferred resistance to ganciclovir was seen in a patient 8 months after renal transplant. We report the off-label use of letermovir with adjunct hyperimmune CMV immunoglobulin in the successful treatment of CMV disease. This report is the first to use this combination for treatment of CMV infection with a high viral load. It contributes to the limited available literature supporting the use of letermovir in the treatment of resistant CMV, where current therapeutic options can be suboptimal due to adverse effects and the risk of cross-resistance.

Topics: Acetates; Antibodies, Viral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Immunoglobulins, Intravenous; Kidney Transplantation; Male; Middle Aged; Mutation; Postoperative Complications; Quinazolines; Viral Load; Viremia

Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV.. Adult patients receiving a kidney or kidney-pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log. Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73-355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5-513] IU/ml vs. 68.7 [range: 34.5-574] IU/ml vs. 78.3 [range: 34.5-347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir-tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml).. In kidney and kidney-pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed.

Topics: Acetates; Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Kidney Transplantation; Quinazolines; Transplant Recipients; Valganciclovir; Viremia

Topics: Acetates; Cytomegalovirus; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Quinazolines; Viremia