Letermovir and maribavir for pan‐resistant cytomegalovirus infection in a patient with haematologic malignancy: Consideration for combination therapy

Abstract

CMV is a double-stranded DNA beta herpes virus that establishes latency after primary infection. CMVi, defined as isolation of the virus or viral proteins or nucleic acid in any body fluid or tissue specimen, in the absence of end-organ disease, 1 is a major complication after allogeneic haematopoietic cell transplant (alloHCT) and associated with increased non-relapse mortality. 2 In the current era of letermovir prophylaxis, early CMVi (infection within first 100 days of HCT) incidence is expected to be low. 3 Late-onset CMVi (after day 100 of HCT) is still a concern upon discontinuation of letermovir, particularly among patients with graft-versus-host disease (GVHD) requiring high dose steroids and/or T cell-depleting therapies, recipients of cord blood or haploidentical HCT. These same risk factors predispose to recurrent and resistant CMVi. 4 AlloHCT patients with recurrent and resistant CMVi pose significant challenges in management. 4 The use of foscarnet for ganciclovir resistant CMVi requires intravenous therapy and is often complicated with nephrotoxicity and electrolyte abnormalities. Cidofovir, used for ganciclovir and foscarnet resistant CMVi, is well-known for its nephrotoxicity. Therapeutic options are limited for pan-resistant CMVi due to UL97 and UL54 mutations that render ganciclovir, foscarnet and cidofovir ineffective. Letermovir, approved for CMV prophylaxis in seropositive alloHCT recipients, has a low viral genetic barrier resistance, and off-label use for salvage therapy for refractory or resistant CMVi should be done with caution. 5 Agents such as leflunomide and artesunate along with CMV-specific T cells have been used with variable success. 4 Maribavir appears to be effective in clinical trial settings for resistant/refractory CMVi; however, resistance is an issue. 4,6 Combination therapy for CMVi

Cytomegalovirus infection in transplant recipients: newly approved additions to our armamentarium

“…Based on its good safety profile and oral formulation, maribavir use may be extended to patients unable to tolerate other anti-CMV agents due to underlying kidney dysfunction and/or myelosuppression, as it was used in the rescue arm in transplant patients who were unable to tolerate IAT in the phase 3 trial (65). On the other hand, and based on in vitro studies (66), some may advocate the use of maribavir in combination with letermovir (67) or other anti-CMV agents (excluding (val)ganciclovir) in complicated refractory CMV infections with or without resistance, or in CMV disease in particular.…”

Maribavir for the Management of Cytomegalovirus in Adult Transplant Recipients: A Review of the Literature and Practical Considerations

“…46 Given alternative mechanisms of action, similar antagonism has not been shown with foscarnet, cidofovir, or letermovir and clinical studies evaluating combination therapy with these nonganciclovir agents exist. [46][47][48] A case report of combination maribavir 400 mg twice daily and letermovir 480 mg daily for pan resistant CMV infection in an allogeneic HSCT recipient has been published. 48 The patient was started on this combination after failing treatment with (val)ganciclovir and foscarnet and demonstrating resistance to (val)ganciclovir, foscarnet, and cidofovir based on a UL54 DNA polymerase mutation via CMV genotypic resistance assay.…”

“…[46][47][48] A case report of combination maribavir 400 mg twice daily and letermovir 480 mg daily for pan resistant CMV infection in an allogeneic HSCT recipient has been published. 48 The patient was started on this combination after failing treatment with (val)ganciclovir and foscarnet and demonstrating resistance to (val)ganciclovir, foscarnet, and cidofovir based on a UL54 DNA polymerase mutation via CMV genotypic resistance assay. Once started on maribavir and letermovir, CMV viral load was undetectable within 3 weeks; viral load remained undetectable while the patient was maintained on letermovir prophylaxis for the next 7 months.…”

“…46 Given alternative mechanisms of action, similar antagonism has not been shown with foscarnet, cidofovir, or letermovir and clinical studies evaluating combination therapy with these nonganciclovir agents exist. 46-48…”