Combination Letermovir and Standard of Care Antiviral for Enhanced Antiviral Response in Cytomegalovirus Infection in Lung Transplant Recipients

Lung transplant recipients are particularly susceptible to CMV infection due to intensive immunosuppressive regimens required to prevent graft rejection. CMV viremia is associated with increased morbidity, including CMV pneumonitis, and may contribute to chronic lung allograft dysfunction (CLAD).Approximately 30-50% of lung transplant recipients develop CMV infection within the first year post-transplant, with higher rates in CMV-seronegative recipients receiving organs from seropositive donors (D+/R-).

Current standard treatment for CMV infection in transplant recipients involves ganciclovir or its oral prodrug, valganciclovir, which inhibit CMV DNA polymerase. While effective, prolonged use is associated with toxicities, including myelosuppression, and the emergence of resistant strains in some cases. Letermovir, a novel antiviral targeting the CMV terminase complex, has shown efficacy in CMV prophylaxis in hematopoietic stem cell transplant recipients, and in kidney transplant recipients. It has now been extensively studied for use in prophylaxis but there are limited data in treatment. It is an attractive drug in transplant recipients because it has an excellent safety profile and requires no dose adjustment for renal dysfunction. However, data on the use of letermovir for treatment (as opposed to prophylaxis) are more limited. A multicenter study of letermovir use for treatment showed reasonable response rates especially in patients with low viral loads. The use of combination therapy for CMV treatment represents an attractive option, as there is extensive experience with other viruses (e.g. HIV , HCV) to show that this strategy leads to improved response rates and lessens the emergence of antiviral resistance. The use of ganciclovir plus letermovir is attractive because they target two different viral enzymes and both have oral options facilitating outpatient treatment. The most recently published international CMV consensus guidelines reports that the use of combination antiviral therapy is a key research need.

The investigators plan to conduct a pilot trial to determine the efficacy of letermovir plus standard of care (SOC) antiviral therapy in clearing CMV infection. The trial will be conducted in compliance with the protocol, Good Clinical Practices (GCP) and the applicable regulatory requirements.

• Proportion of patients achieving an undetectable viral load [Срок оценки: At week 3 and by month 6 after enrolment]
• Proportion of patients achieving CMV viral load <137 IU/mL (lower limit of quantification of the assay) [Срок оценки: At week 3 from enrolment and at 6 months]
• Time to clearance of CMV viremia [Срок оценки: From enrolment until clearance of CMV viremia, up to 6 months after enrolment]
• Time to resolution of symptoms if present [Срок оценки: From enrolment until clearance of symptoms, up to 6 months after enrolment]
• Development of antiviral resistance [Срок оценки: From enrolment until up to 6 months after enrolment]
• Incidence of adverse events [Срок оценки: From enrolment until up to 6 months after enrolment]
• Proportion of patients with clinically significant CMV recurrence within 6months, as determined by quantitative PCR or symptomatic CMV disease [Срок оценки: From enrollment until 6 months.]
• Monthly enrollment rate as a measure of recruitment feasibility [Срок оценки: From start of enrollment until up to 6 months after the final patient is enrolled]