Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection
Condition: Cytomegalovirus Infections
MeSH terms: Infections; Communicable Diseases; Cytomegalovirus Infections
Intervention: Letermovir
Intervention description: Patients will receive intravenous or oral letermovir at a dose of 480mg/day.
Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment.
For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day.
Intervention MeSH terms: Letermovir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Cytomegalovirus Infections; CMV

Summary:

      The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active
      cytomegalovirus infection or cytomegalovirus disease in patients with infections that are
      refractory or resistant to available treatments or who are experiencing organ dysfunction
      that makes unsafe the use of available antiviral treatments.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥12 years

          -  Weight ≥30 kg

          -  Transplant recipient (HCT, SOT) or other immunocompromised patients including those
             with HIV infection that require antiviral treatment for CMV.

          -  Documented CMV disease or persistent CMV infection (CMV virus load above 500 IU/mL on
             consecutive measurements, at least one day apart).

          -  CMV infection is refractory to treatment (defined as ≥14 days of standard CMV
             treatment without clinical improvement for CMV disease, or failure to achieve >1 log
             reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17

          -  Current CMV infection has documented genotypic resistance to ganciclovir or foscarnet.

          -  For patients with any prior CMV infection episode that broke through letermovir
             prophylaxis, but not during the current CMV infection, documentation of letermovir
             susceptibility testing should demonstrate absence of letermovir mutations known to
             confer resistance to letermovir.

          -  Severe myelosuppression (ANC <1000/µL, Hemoglobin <8g/dL, or Platelets <25,000/µL)17
             or renal dysfunction (estimated creatinine clearance <60 mL/min by MDRD in adults or <
             60 ml/min/1.73 m2 by bedside Schwartz equation in < 18 years-old) at baseline or which
             develops during antiviral treatment.

             --Patients who develop severe myelosuppression or renal dysfunction during antiviral
             treatment as defined above are eligible without having to meet the
             refractoriness/antiviral resistance criterion.

          -  Combinations of genotypic antiviral resistance and organ dysfunction that lead to
             eligibility are presented in the full protocol eligibility table.

          -  The effects of letermovir on the developing human fetus are unknown. For this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (barrier method of birth control; abstinence) prior to study entry, for the duration
             of study participation, and 3 months after completion of letermovir administration.
             Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately. Men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 3 months after
             completion of letermovir administration.

             --Patients of childbearing potential must have a negative serum or urine pregnancy
             test.

          -  Able to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to letermovir.

          -  Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at screening.

          -  Acute liver injury at baseline meeting Hy's law.

          -  Current CMV infection broke through letermovir prophylaxis.

          -  Patients with life expectancy of less than a week. Determination of life expectancy
             will be discussed with the patient's primary treatment physician.

          -  Patient taking strong inhibitors or inducers of hepatic CYP enzymes including
             rifampicin, phenytoin, clarithromycin, ritonavir, or cobicistat.

          -  HIV patients who are receiving antiretroviral treatment protease inhibitors
             (darunavir, lopinavir, etc) whether by themselves or boosted with ritonavir or
             cobicistat, or HIV patients receiving cyclosporine treatment due to strong drug-drug
             interactions.

          -  Combinations of genotypic antiviral resistance and organ dysfunction that do not meet
             eligibility criteria are described in the full protocol eligibility table.