Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report

Pearston, Aaron P.; Ingemi, Amanda I.; Ripley, Kathryn; Wilson, Tyler J.; Gruber, Jacqueline; McMahon, Megan; Sutton, Sharon E.; Khardori, N.M.

doi:10.1016/j.transproceed.2021.02.001

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…6 ) supporting the use of mAbs in combination with small molecules inhibitors. In a recently published case study, a combination of letermovir and HIG was used to successfully treat a ganciclovir-resistant strain of HCMV in a renal transplant recipient 75 giving credence to the therapeutic paradigm of mAb/drug combinations. Combination therapy may lower the required dose of antiviral drugs such as ganciclovir and letermovir and limit the associated toxicity and emergence of viral mutations, as a combination approach would be expected to effectively limit virus replication and associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH

et al. 2022

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Human cytomegalovirus (HCMV) is a β-herpesvirus that increases morbidity and mortality in immunocompromised individuals including transplant recipients and newborns. New anti-HCMV therapies are an urgent medical need for diverse patient populations. HCMV infection of a broad range of host tissues is dependent on the gH/gL/gO trimer and gH/gL/UL28/UL130/UL131A pentamer complexes on the viral envelope. We sought to develop safe and effective therapeutics against HCMV by generating broadly-neutralizing, human monoclonal antibodies (mAbs) from VelocImmune® mice immunized with gH/gL cDNA. Following high-throughput binding and neutralization screening assays, 11 neutralizing antibodies were identified with unique CDR3 regions and a high-affinity (KD 1.4-65 nM) to the pentamer complex. The antibodies bound to distinct regions within Domains 1 and 2 of gH and effectively neutralized diverse clinical strains in physiologically relevant cell types including epithelial cells, trophoblasts, and monocytes. Importantly, combined adminstration of mAbs with ganciclovir, an FDA approved antiviral, greatly limited virus dissemination. Our work identifies several anti-gH/gL mAbs and sheds light on gH neutralizing epitopes that can guide future vaccine strategies.

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Section: Discussionmentioning

confidence: 99%

Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH

et al. 2022

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“…Unfortunately although well tolerated overall, letermovir monotherapy and combination with other currently available CMV‐active antivirals has had variable success, and its use has been associated with rapid development of letermovir resistance mutations. Please see Table 4 for a summary of the literature to date describing the use of letermovir for the treatment of CMV in SOT recipients 2,3,6,7,13–19 . Despite these limitations, the addition of letermovir to valganciclovir in the setting of low‐level refractory CMV is a logical concept to address a potential resistant sub‐population while continuing to treat the wild‐type subset without requiring conversion to alternative antivirals such as foscarnet, which are associated with significant toxicity, and require intravenous access.…”

Section: Discussionmentioning

confidence: 99%

“…Please see Table 4 for a summary of the literature to date describing the use of letermovir for the treatment of CMV in SOT recipients. 2,3,6,7,[13][14][15][16][17][18][19] Despite these limitations, the addition of letermovir to valganciclovir in the setting of low-level refractory CMV is a logical concept to address a potential resistant sub-population while continuing to treat the wild-type subset without requiring conversion to alternative antivirals such as foscarnet, which are associated with significant toxicity, and require intravenous access. This approach would be also be theoretically preferrable over high-dose valganciclovir for subclinical resistance, as significant myelosuppression can occur with aggressive (val)ganciclovir dosing.…”

Section: Discussionmentioning

confidence: 99%

The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients

Jorgenson

Descourouez

Garg

et al. 2021

Transplant Infectious Dis

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Purpose 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. Methods 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 (log10 < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. Results 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). Conclusion 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.

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“…101 It is often used as a multipronged strategy in the treatment of refractory or resistance, or when other therapies are not tolerated, with varying success documented. 3,[102][103][104] Neutralizing monoclonal antibodies derived from CMVseropositive patients have been isolated and are attractive future treatment candidates for CMV prevention and treatment. 105 Administration of a combination of 2 neutralizing antibodies to CMV (RG7667) was evaluated in kidney CMV-seronegative kidney transplant recipients in a phase 2A clinical trial (n = 120).…”

Section: Immunoglobulinsmentioning

confidence: 99%

What’s New: Updates on Cytomegalovirus in Solid Organ Transplantation

Stewart,

Kotton

2023

Transplantation

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Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may be worsening with the proportion of high-risk D+/R− solid organ transplantation recipients increasing in some regions globally. Cohort studies continue to support either universal prophylaxis or preemptive therapy as effective prevention strategies. Letermovir prophylaxis was noninferior to valganciclovir in adult high-risk D+/R− kidney transplant recipients with fewer drug-related adverse events in a recent clinical trial and has now been approved for such use in some regions. Maribavir preemptive therapy failed to demonstrate noninferiority when compared with valganciclovir in hematopoietic stem cell transplant recipients but looked promising for safety. Donor matching could be useful in prevention CMV disease with a survival advantage demonstrated in seronegative recipients waiting up to 30 mo for a seronegative kidney. Immune-guided prophylaxis resulted in fewer CMV infection episodes in lung transplant recipients when compared with fixed-duration prophylaxis in a recent clinical trial. For treatment of refractory or resistant CMV infection, maribavir was more efficacious and better tolerated when compared with investigator-initiated therapy in its registration trial for this condition. Further research regarding best treatment and prophylaxis of resistant or refractory CMV infection is needed to reflect best clinical practice choices. Optimal use of immune globulin or CMV-specific T cells for prevention or treatment of CMV disease remains undefined. Standardized definitions for the design of CMV clinical trials have been developed. In this review, we highlight recent updates in the field from data published since 2018.

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Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report

Cited by 8 publications

References 12 publications

Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH

Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH

The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients

What’s New: Updates on Cytomegalovirus in Solid Organ Transplantation

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