Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study
2021; Elsevier BV; Volume: 21; Issue: 10 Linguagem: Inglês
10.1111/ajt.16718
ISSN1600-6143
AutoresTobias Veit, Dieter Munker, Jürgen Barton, Katrin Milger, Teresa Kauke, Bruno Meiser, Sebastian Michel, Michael Zöller, Hans Nitschko, Oliver T. Keppler, Jürgen Behr, Nikolaus Kneidinger,
Tópico(s)Herpesvirus Infections and Treatments
ResumoAmerican Journal of TransplantationVolume 21, Issue 10 p. 3449-3455 BRIEF COMMUNICATIONOpen Access Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study Tobias Veit, Tobias Veit Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorDieter Munker, Dieter Munker orcid.org/0000-0001-5471-578X Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorJürgen Barton, Jürgen Barton Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorKatrin Milger, Katrin Milger orcid.org/0000-0003-2914-8773 Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorTeresa Kauke, Teresa Kauke Laboratory for Immunogenetics, University of Munich, LMU, Munich, Germany Department of Thoracic Surgery, University of Munich, LMU, Munich, GermanySearch for more papers by this authorBruno Meiser, Bruno Meiser Transplant Center, University of Munich, LMU, Munich, GermanySearch for more papers by this authorSebastian Michel, Sebastian Michel Clinic of Cardiac Surgery, University of Munich, LMU, Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorMichael Zoller, Michael Zoller Department of Anaesthesiology, University of Munich, LMU, Munich, GermanySearch for more papers by this authorHans Nitschko, Hans Nitschko Max von Pettenkofer Institute and Gene Center, Virology, German Center for Infection Research, Partner Site Munich, National Reference Center for Retroviruses, LMU, Munich, GermanySearch for more papers by this authorOliver T. Keppler, Oliver T. Keppler Max von Pettenkofer Institute and Gene Center, Virology, German Center for Infection Research, Partner Site Munich, National Reference Center for Retroviruses, LMU, Munich, GermanySearch for more papers by this authorJürgen Behr, Jürgen Behr Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorNikolaus Kneidinger, Corresponding Author Nikolaus Kneidinger nikolaus.kneidinger@med.uni-muenchen.de orcid.org/0000-0001-7583-0453 Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany Correspondence Nikolaus Kneidinger, Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Germany. Email: nikolaus.kneidinger@med.uni-muenchen.deSearch for more papers by this author Tobias Veit, Tobias Veit Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorDieter Munker, Dieter Munker orcid.org/0000-0001-5471-578X Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorJürgen Barton, Jürgen Barton Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorKatrin Milger, Katrin Milger orcid.org/0000-0003-2914-8773 Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorTeresa Kauke, Teresa Kauke Laboratory for Immunogenetics, University of Munich, LMU, Munich, Germany Department of Thoracic Surgery, University of Munich, LMU, Munich, GermanySearch for more papers by this authorBruno Meiser, Bruno Meiser Transplant Center, University of Munich, LMU, Munich, GermanySearch for more papers by this authorSebastian Michel, Sebastian Michel Clinic of Cardiac Surgery, University of Munich, LMU, Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorMichael Zoller, Michael Zoller Department of Anaesthesiology, University of Munich, LMU, Munich, GermanySearch for more papers by this authorHans Nitschko, Hans Nitschko Max von Pettenkofer Institute and Gene Center, Virology, German Center for Infection Research, Partner Site Munich, National Reference Center for Retroviruses, LMU, Munich, GermanySearch for more papers by this authorOliver T. Keppler, Oliver T. Keppler Max von Pettenkofer Institute and Gene Center, Virology, German Center for Infection Research, Partner Site Munich, National Reference Center for Retroviruses, LMU, Munich, GermanySearch for more papers by this authorJürgen Behr, Jürgen Behr Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanySearch for more papers by this authorNikolaus Kneidinger, Corresponding Author Nikolaus Kneidinger nikolaus.kneidinger@med.uni-muenchen.de orcid.org/0000-0001-7583-0453 Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany Correspondence Nikolaus Kneidinger, Department of Internal Medicine V, University Hospital, LMU, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Germany. Email: nikolaus.kneidinger@med.uni-muenchen.deSearch for more papers by this author First published: 12 June 2021 https://doi.org/10.1111/ajt.16718AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log10) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account. Abbreviations BW body weight CMV cytomegalovirus CMVIgG i.v. CMV-immune globulins FK-506 tacrolimus HSCT hematopoietic stem cell transplant MMF mycophenolate mofetile PCR polymerase chain reaction SOT solid organ transplantation 1 INTRODUCTION Cytomegalovirus (CMV) is the leading opportunistic infection in solid organ transplant (SOT) and allogenic hematopoietic stem cell transplant (HSCT) recipients.1-3 In lung transplant recipients, infection is associated with graft failure and decreased overall survival.4 Antiviral drugs are the mainstay for the prevention and therapy of CMV infection and disease. Universal prophylaxis with valganciclovir is currently the most widely used strategy to prevent CMV infections.5 However, ganciclovir and its prodrug valganciclovir are associated with several side effects, most notably neutropenia.6 Recently, research has shown that lung transplant outcomes are influenced by the severity of neutropenia and the subsequent use of granulocyte colony-stimulating factor.7 Furthermore, prolonged use of CMV antiviral drugs poses the risk for the development of antiviral drug resistance resulting in treatment failure.8 Antiviral-resistant or refractory CMV infection is challenging, and salvage therapies are associated with significant toxicities and high costs, indicating the need for new therapeutic options. Previous studies about the efficacy of foscarnet in transplant recipients treated for ganciclovir-resistant or refractory CMV infection have shown that outcomes are suboptimal, in terms of virological clearance, renal dysfunction, and mortality.9 Foscarnet and cidofovir are highly associated with metabolic disturbances and nephrotoxicity.9 Letermovir, a viral terminase inhibitor, was recently approved for CMV prophylaxis in seronegative allogeneic HSCT recipients.10 The use of letermovir for prophylaxis or therapy of CMV infection in SOT is not yet approved. Recently, mixed results of SOT recipients receiving letermovir for CMV infection have been reported.11-20 Therefore, we provide our perspective on the potential role of letermovir in the treatment of ganciclovir-resistant or refractory CMV infection and disease in lung transplant recipients. 2 METHODS 2.1 Study cohort All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for difficult to treat CMV infection, were included in this study and analyzed retrospectively. Rescue therapy for difficult to treat CMV infection was initiated on request of the treating physician in case of ganciclovir-resistant or refractory CMV infection and ganciclovir-associated side effects, respectively. Refractory CMV infection was defined as (1) increasing CMV viral load after at least 2 weeks of appropriately dosed antiviral therapy and (2) lack of improvement or progression of CMV end-organ disease after at least 2 weeks of appropriately dosed antiviral therapy as described previously.8 Before each treatment attempt, a cost coverage for off label use of letermovir was applied and approved by the patient's respective health insurance company. Patients were retrospectively classified according to their therapy response to letermovir into “Responder” and “Non-Responder.” Responders were defined as patients with significant log10 decrease (i.e., ≥1 log10) of viral load after 4 weeks of antiviral therapy. Non-Responders (treatment failure) were defined as followed: (1) persistent viral load after 4 weeks of antiviral therapy without significant log10 decrease (i.e., 10 spots IE-1 and/or >10 spots pp-65. 2.3 Statistical analysis Continuous variables are presented as the mean ± standard deviation and median (Q1, Q3), with categorical variables summarized by frequency and percentage. Data were statistically analyzed by SPSS version 24.0 (IBM SPSS) statistical software. 3 RESULTS 3.1 Study cohort From 230 lung transplant recipients between March 2018 and August 2020, we identified 28 (12.2%) patients who received letermovir as therapy for difficult to treat CMV infection. Characteristics of the study cohort are summarized in Table 1. Lung transplant recipients experienced a median of 2.0 [1.0–3.0] CMV infections and were at least once admitted to our hospital for i.v. ganciclovir and CMVIgG before rescue therapy was initiated. Detailed information about all antiviral interventions and mutations conferring ganciclovir resistances is provided as supplementary material (Tables S1 and S2). TABLE 1. Patient characteristics All (n = 28) Age (years) 53.7 ± 8.5 Sex (male), n (%) 13 (46.4) BMI (kg/m2) 22.6 ± 4.0 Underlying diseases COPD, n (%) 13 (46.4) ILD, n (%) 10 (35.7) CF, n (%) 4 (14.3) Others, n (%) 1 (3.6) CMV-serostatus, n (%) D+/R− 25 (89.3) D+/R+ 3 (10.7) Induction therapy, n (%) 0 (0.0) Maintenance immunosuppression, n (%)a a Immunosuppression before initiation of rescue therapy. FK-506 + MMF + prednisone 19 (67.9) Cyclosporine + MMF + prednisone 4 (14.3) FK-506 + MMF + prednisone + mTORb b Everolimus or Sirolimus. 5 (17.8) Ganciclovir-resistance, n (%) 12 (42.8) UL 97 gene mutation 10 (35.7) UL 97 + UL 54 gene mutation 2 (7.1) CMV disease: organs, n (%)/patients, n (%) 16 (57.1)/15 (53.6) CMV pneumonitis 3 (10.7) CMV gastritis/esophagitis 7 (25.0) CMV colitis 5 (17.9) CMV encephalitis 1 (3.6) Time from transplantation to letermovir (months) 20.7 ± 26.2 Note Data are presented as mean ± standard deviation and number and percentage, respectively. Abbreviations: BMI, body mass index; CF, cystic fibrosis; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; FK-506, tacrolimus; ILD, interstitial lung diseases; LTx, lung transplantation; MMF, mycophenolate mofetile. a Immunosuppression before initiation of rescue therapy. b Everolimus or Sirolimus. Simultaneously (±4 weeks) to initiation of letermovir in 10 patients (35.7%), one or more additional antiviral interventions were performed. In 18 patients (64.3%), no further action was taken in this time frame. Simultaneous interventions were as follows: addition of CMVIgG (n = 5), addition of CMVIgG and reduction of MMF dose (n = 3), switch to mTOR-inhibitor-based quadruple low tacrolimus immunosuppression regimen (n = 1) and switch to mTOR-inhibitor-based quadruple low tacrolimus immunosuppression regimen and addition of CMVIgG (n = 1). In total, 15 patients (53.6%) had CMV disease at the time of switch to letermovir as shown in Table 1. 3.2 Efficacy of letermovir and concomitant therapy The course of CMV viral load before and after initiation of letermovir is depicted in Figure 1. In 23 patients (82.1%), referred to as “responder,” CMV-viral load could be significantly (i.e., ≥1 log10) decreased after at a median of 17 [14–27] days upon initiation of letermovir and cleared subsequently after a median of 32 [25–64] days in all of these patients. In all patients with CMV disease, symptoms significantly improved. Thereof, in four patients, improvement was confirmed by histology. In responders, letermovir was stopped at a median of 63 [33–135] days after the first negative CMV-PCR. Thereof, six patients (26.1%), in whom letermovir had been stopped due to a rapid response 44 [31–61] days after the last negative PCR, experienced relapse of CMV. All patients were successfully retreated with letermovir. FIGURE 1Open in figure viewerPowerPoint Course of CMV viral load before and after initiation of letemovir. (A) All patients (n = 28); (B) responder without relapse (n = 17); (C) responder with relapse (n = 6); (D) non-responder (n = 5). Data are provided as mean and quartiles 1 and 3 (A, B) and as exact individual viral load trajectories (C, D). The horizontal dashed line indicates the threshold for quantitative detection of CMV plasma DNA by the assays used in this series (137 IU/ml) Five patients (17.9%) were classified as “non-responder” due to (1) delayed treatment response and subsequent increased of viral load (i.e., ≥1 log10) over the course of treatment (n = 1, 20%); (2) CMV end-organ disease developed (n = 1, 20%); (3) a mutation associated with letermovir resistance developed (n = 3, 60%). Courses of non-responder were as follows: in one patient, CMV-viral load persisted (i.e., <1 log10 decrease) for 66 days upon initiation of letermovir and increased (3.4 log10) approximately 4 months of initiation of letermovir. Test for letermovir resistance was not performed because viral load decrease continuously after application of CMVIgG. One patient received concomitant anthracycline-based chemotherapy for Kaposi sarcoma. Although CMV-PCR in serum remained low, the patient developed necrotizing CMV retinitis while receiving letermovir. Three patients developed mutation of the CMV UL56 terminase associated with letermovir resistance (UL-56-Gen: C325Y). Thereof, two patients suffered from significant persistent concomitant diarrhea due to norovirus and campylobacter infection respectively. One patient did respond but relapsed despite regular use of letermovir after approximately 2 months of therapy. At the time of confirmation of letermovir resistance, the previous recorded UL97 ganciclovir resistance could not be found anymore, and the patient was successfully re-challenged to valganciclovir. Further detailed information about non-responder is provided in the supplementary material (Table S3). Absolute lymphocyte count at the time of letermovir initiation was available in 23 patients (82.1%). There was no statistical significant difference between responder and non-responder (1.26 ± 1.01 vs. 0.78 ± 0.72 109/L; p = .330) and between responder with and without relapse (1.74 ± 1.56 vs. 1.08 ± 0.71 109/L; p = .267). Assessment of CMV-specific immunity was available in only a minority of patients. Results are provided in the supporting information. There was no difference of the CMV viral load at the time of letermovir initiation between responder and non-responder (Table S1). We stratified our patients according to viral load in patients with ≥10 000 IU/ml (n = 14) and patients 80%) of patients with treatment failure upon (val)ganciclovir, letermovir was effective to treat CMV infection and disease alone or in combination with other antiviral interventions. Significant comorbidities may be associated with treatment failure and the development of mutation conferring letermovir resistance. Letermovir was applied as described for the prophylaxis in HSCT recipients but demonstrated therapeutic potential in CMV-infection and disease.10 Letermovir was used alone or in combination with other antiviral interventions, like administration of CMVIgG and adjustment of immunosuppressive therapy. Therefore, the beneficial effect on CMV viral load cannot solely attributed to letermovir and has to be regarded in the context of several previous and simultaneous antiviral measures. In patients responding to letermovir CMV viral load could be significantly (i.e., ≥1 log10) decreased after approximately 2–3 weeks and subsequent viral clearance could be observed. Therefore, a 4-week period seems to be suitable to effectively judge treatment response. This is in contrast to the current definition of refractory CMV infection where a persistent viral load with 2 weeks of appropriately dosed currently available antiviral therapy is classified as probable refractory disease.8 Whether this is attributed to the mode of action of letermovir and whether measurement of CMV-pp65 as a marker of active viral replication might be an additional tool to assess early treatment response has to be explored. In a multicenter case series, success rates of letermovir were significantly lower in patients with higher viral loads at letermovir initiation.20 In our cohort, no clear difference between patients with lower and higher viral loads was observed, whereas in patients with high viral load a significant reduction of the viral load was achieved faster, time to complete clearance tended to be longer compared with patients with lower viral load. Optimal duration of letermovir therapy upon viral clearance has to be assessed. Treatment duration was varying in our study, which was based on clinical grounds and insurance coverage. As suggested previously, in all patients responding to letermovir, treatment was continued until clearance of CMV viral load and was continued for a median of approximately 2 months after the first negative CMV-PCR.23 In six patients, rapid viral clearance resulted in an early discontinuation of letermovir. However, in all patients with CMV relapse after letermovir discontinuation, retreatment with letermovir was again successful. Immune monitoring by CMV-specific immunity assays, or absolute lymphocyte count may be useful tools to assess the duration of therapy. Approximately 18% of patients did not respond to salvage therapy with letermovir. The number of patients was too low to identify differences to responder and risk factors for treatment failure. However, a significant number of patients had accompanying disease potentially complicating management. Noticeable, two patients who developed resistance to letermovir suffered from long-lasting diarrhea, potentially indicating a reduce drug absorption and therefore subobtimal dosage of letermovir. Both patients developed a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring a resistance to letermovir.18 It has been suggested that letermovir may have a low viral genetic barrier to resistance.24 Suboptimal dosage or prolonged uncontrolled low-level CMV-viremia may facilitate development of resistances, which is in line with our observations.25 In our study, the decision to use letermovir in a dose as described for the prophylaxis of CMV infection in HSCT was based on the safe use in this patient population as reported in large RCT and the lack of an approved therapeutic dose.10 Furthermore, the optimal appropriate therapeutic dose remains unknown. Higher doses of letermovir (720–960 mg) have been used successfully in patients with drug-resistant CMV retinitis and were well tolerated.17 In our cohort, one patient developed necrotizing CMV retinitis, whereas CMV-PCR in serum remained low. This indicates the development of compartmentalized resistance, which might have been prevented by higher doses of letermovir. Furthermore, intravenous formulation might be of use in patients where drug absorption is limited, and higher bioavailability is intended. The combination of letermovir with valganciclovir has been successfully applied in a patient with difficult to treat CMV infection suggesting the potential role of combination of two or more antiviral drugs.19 In this respect, preliminary results of a phase 3 randomized trial (NCT02931539) demonstrated that maribavir, another new CMV-active agent, was superior to currently available drugs in transplant recipients with refractory or resistant CMV infection.26 No head to head comparison of maribavir and letermovir has been performed. Both drugs seem to be useful in the context of difficult to treat CMV infection and neither exhibits myelotoxicity or nephrotoxicity. Both agents have unique mechanisms of action limiting cross-resistance, and synergy was observed when maribavir was administered with letermovir.27, 28 Reported side effects were mild and mostly of gastrointestinal nature (e.g., nausea, vomiting, and diarrhea). None of the patients developed atrial fibrillation or flutter as reported previously.10 Myelotoxic and nephrotoxic events did not occur. Other currently available antiviral drugs like foscarnet and cidofovir are associated with significant metabolic changes and nephrotoxicity.9 Furthermore, intravenous administration limits the use in an outpatient setting. Lung transplant patients receive immunosuppressive drugs with narrow therapeutic ranges. Coadministration with cyclosporine doubles letermovir plasma concentration; therefore, a reduction of the clinical dosage of letermovir to 240 mg is recommended.29 On the other side, dose adjustment of calcineurin- and mTOR-inhibitors upon initiation of letermovir was mandatory in our study, indicating the importance of therapeutic drug monitoring in this setting. The results of our study should be interpreted in view of the study design and its limitations, which include a retrospective, single-center setting, and a small study population without control group. In a significant number of patients, several antiviral measures have been taken over the course of disease, and the beneficial effect on CMV viral load cannot solely be attributed to letermovir. Furthermore, concomitant development of CMV-specific immunity in this time frame cannot be excluded. Finally, the threshold to use letermovir for difficult to treat CMV infection likely has changed over time, whereas initially, letermovir was used after salvage therapies including the use of foscarnet, over the time letermovir has been used earlier in the course of disease and has replaced foscarnet as second line antiviral drug of choice in our center. In conclusion, we have shown that letermovir was well tolerated and effective in treating CMV-infections in lung transplant recipients failing on currently available antiviral agents. In patients not responding to therapy letermovir resistance should be taken into account. DISCLOSURE The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Nikolaus Kneidinger received personal fees from MSD outside the submitted work. The other authors have no conflict of interests to disclose. Open Research DATA AVAILABILITY STATEMENT Data are available on request from the authors. Supporting Information Filename Description ajt16718-sup-0001-Supinfo.docxWord document, 35.6 KB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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